β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives and preparation methods same and use in aspects of preventing and treating plant viruses, fungicides and insecticides

ABSTRACT

The present invention relates to β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives (I) and a method for preparing same and the use in the aspects of preventing and treating plant viruses, fungicides and insecticides. For the meaning of each group in formula (I) see the description. The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives of the present invention show a particularly ourstanding anti-plant virus activity, and also have fungicidal and insecticidal activities.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 USC § 371 national stage application ofPCT/CN2014/094847, which was filed Dec. 24, 2014 and claims priority toChinese Patent Application No. 201310752240.2, filed Dec. 30, 2013,entitled “β-Carboline, Dihydro-β-Carboline and Tetrahydro-β-CarbolineAlkaloid Derivatives and Preparation Methods Same and Use in Aspects ofPreventing and Treating Plant Viruses, Fungicides and Insecticides,”both of which are incorporated specifically and entirely herein byreference as if fully set forth.

FIELD OF THE INVENTION

The present invention relates to β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloid derivatives and their preparationmethods and use in the preventing and treating plant viruses fungicidesand insecticides and pertains to the technical field of pesticides.

BACKGROUND OF THE INVENTION

The skeleton structures of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline widely exist in natural products and drugmolecules. Harmine and tetrahydroharmine belong to β-carboline andtetrahydro-β-carboline alkaloids respectively and are representativecompounds of harmala alkaloids. Harmine was first separated from P.harmala L. This alkaloid shows cytotoxicity to leukemia cell lines HL60and K562. Tetrahydroharmine is a fluorescent molecule separated fromMalpighiacease plant Banisteriopsis caapi. This compound has weakinhibition to the re-uptake of 5-hydroxytryptamine. Harmaline is anagonist of the central nervous system and a reversible inhibitor ofmonoamine oxidase (MAO-A).

Currently, the research on β-carboline, dihydro-β-carboline andtetrahydro-β-carboline and substances similar to them focuses onanti-tumor, killing of human parasites and monoamine oxidase inhibitors.However, as far as we know, no document reports the activity ofβ-carboline, dihydro-β-carboline and tetrahydro-β-carboline andsubstances similar to them against plant viruses, and little wasreported on their bactericidal activity and insecticidal activity. Inthe aspect of bactericidal activity: Fu Haibo et al from GansuAgricultural University researched and found in 2007 that the extractingsolutions of P. harmala L. in different solvents all have certaininhibiting effect to spore germination of four kinds of pathogenicbacteria, including Botrytis cinerea, Fusarium oxysporum, Alternariasolani and Cladosporium cucumerinum Ellis et Arthur, and their EC₅₀ is0.060, 0.199, 0.105 and 0.223 g/mL respectively (Fu Haibo, Ding Defang,Zhao Hongmei, Yang Shunyi, Grassland and Lawn, 2008, 1, 44-48); in 2007,Wen Ren et al from Fudan University reported derivatives with astructure of 1-(3-indol)-1,2,3,4-tetrahydro-β-carboline and researchedthe in vitro activity of these derivatives against Pyricularia oryzae(CN101020688); in 2011, Zhang Yaomou et al from South China AgriculturalUniversity reported compounds with a structure of β-carboline-3-oximeester and meanwhile studied the inhibitory activity of these compoundsagainst Colletotrichum musae, Colletotrichum gloeosporioides and tomatolate plight (Lu Shaoying, Zhang Yaomou, Synthetic Chemistry, 2011, 19(6), 769-772); in 2012, this research group again reported compoundswith a structure of 1-p-trifluoromethylphenyl-β-carboline-3-carbonylbishydrazide, but the quantity of the compounds was small and theirbacteriostatic activity against Rhizoctorzia solani was tested only (CaiYing, Huang Jianfeng, Zhang Meidan, Zeng Yong, Zhang Yaomo, SyntheticChemistry, 2012, 20(6), 736-739.). In the aspect of insecticidalactivity: in 2005, Zhao Xiaomeng et al from Beijing University ofAgriculture reported the contact activity of the ethanol extract,chloroform extract and water extract of the overground part of P.harmala L. in the growing period against Myzus persicae, Macrosiphumrosivorum and Tetranychus cinnabarinus. The result is that their contactactivity against spider mites is all above 95% at concentration of 10mg/mL, and that against two kinds of aphids is above 70% atconcentration of 10 mg/mL (Zhao Xiaomeng, Zeng Zhaohai, ChineseAgricultural Science Bulletin, 2005, 21(4), 278-279); in 2010, ZhongGuohua et al from South China Agricultural University reported theinsecticidal activity of 1,3-disubstituted β-carboline andtetrahydro-β-carboline derivatives against culex pipiens larvae andLipaphis erysimi. To be specific, the LC₅₀ of the compounds with astructure of 1-phenyl substituted β-carboline andtetrahydro-β-carboline-3-methyl ester against culex pipiens larvae is20.82 mg/L and 23.98 mg/L respectively, and the LC₅₀ against Lipaphiserysimi is 53.16 mg/L and 68.05 mg/L respectively (Zeng, Y; Zhang, Y M.;Weng, Q. F.; Hu, M. Y.; Zhong G H. Molecules 2010, 15, 7775-7791).

SUMMARY OF THE INVENTION

The object of the present invention is to provide β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives andtheir preparation methods and use in the preventing and treating plantviruses and killing of bacteria and insects. The β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivativesdescribed in the present invention show very good activity against plantviruses and also show bactericidal activity and insecticidal activity.The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloidderivatives described in the present invention are compounds with astructure shown in the following general formula (I):

The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloidderivatives (I) described in the present invention are compounds withstructures shown in the following four general formulas (I_(a), I_(b),I_(c), I_(d)):

The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloidderivatives (I) described in the present invention further comprisenatural compounds with structures shown in the following formulae:

The dihydro-β-carboline alkaloid described in the present invention maybe prepared by the following method (Path 1): firstly introducingaldehyde group to indol 3-site to obtain compound 1, the compound 1 thenreacts with nitromethane and ammonium acetate to obtain intermediate 2,the intermediate 2 is reduced to obtain tryptamine 3, and then thetryptamine 3 is acylated and cyclized to obtain dihydro-β-carbolinealkaloid harmalan.

Path 1:

The β-carboline and tetrahydro-β-carboline alkaloid described in thepresent invention may be prepared by the following method (Path 2):firstly, reacting tryptamine 3 with an acetaldehyde aqueous solutionunder the catalysis of sulfuric acid to obtain tetrahydro-β-carbolinealkaloid tetrahydroharmane, which is then further dehydrogenated by onestep and oxidized to obtain β-carboline alkaloid harmane.

Path 2:

The tetrahydro-β-carboline alkaloid described in the present inventionmay be prepared by the following method (Path 3): firstly, reactingharmine with benzyl bromide to obtain quaternary ammonium salt 4, whichis then reduced to obtain compound 5; lastly, the compound 5 ishydrogenated under the catalysis of Pd/C to obtaintetrahydro-β-carboline alkaloid tetrahydroharmine.

Path 3:

The β-carboline alkaloid described in the present invention may beprepared by the following method (Path 4): Harmine is demethylated underacidic condition to obtain β-carboline alkaloid harmol.

Path 4:

The β-carboline alkaloid derivatives (I_(a)) described in the presentinvention may be prepared by the following method (Path 5): reactingHarmane with bromosuccinimide under acidic condition to obtain compoundsI_(a)-1 and I_(a)-2, and reacting the obtained compounds with sodiumnitrate under acidic condition to obtain compounds I_(a)-3 and I_(a)-4containing substituted nitro on phenyl ring.

Path 5:

The β-carboline alkaloid derivatives (I) described in the presentinvention may be prepared by the following method (Path 6): reactingHarmol with isocyanate to obtain compound I_(a)-5, reacting Harmol withacyl chloride to obtain compound I_(a)-6-I_(a)-8, and reacting Harmolwith amino acid in presence of a condensation agent to obtain compoundI_(a)-9.

Path 6:

The β-carboline and tetrahydro-β-carboline alkaloid derivatives (I_(a)and I_(b)) described in the present invention may be prepared by thefollowing method (Path 7): firstly, reacting L-tryptophan with anacetaldehyde aqueous solution to obtain cyclization product I_(b)-1,which is then further esterified by one step to obtain compoundI_(b)-13. Compound I_(b)-13 is dehydrogenated and oxidized to obtaincompound I_(a)-10. Compound I_(a)-10 is hydrolyzed under alkalinecondition to obtain compound I_(a)-11. Compound I_(a)-10 is reduced bylithium aluminum hydride to obtain compound I_(a)-12. The compound isoxidized to obtain aldehyde I_(a)-13. Compound I_(a)-13 reacts withmalonic acid to obtain acrylic acid I_(a)-14. By a same path, compoundI_(a)-15-I_(a)-16 can be synthesized.

Path 7:

The tetrahydro-β-carboline alkaloid derivatives (I_(b)) described in thepresent invention may be prepared by the following method (Path 8):L/D-tryptophan takes Pictet-spengler reaction with fatty aldehyde oraromatic aldehyde under acidic or alkaline condition to obtain acidsI_(b)-1-I_(b)-6, and acids I_(b)-1-I_(b)-6 are further esterified toobtain ester I_(b)-7-I_(b)-12.

Path 8:

The dihydro-β-carboline alkaloid derivatives (I_(b)) described in thepresent invention may be prepared by the following method (Path 9):reacting L-tryptophan with ethanol to obtain ethyl ester 6, which isacylated and then reacting with phosphorus oxychloride to obtaindihydro-β-carboline alkaloid derivative I_(b)-14.

Path 9:

The tetrahydro-β-carboline alkaloid derivatives (I_(b)) described in thepresent invention may be prepared by the following method (Path 10):reacting methyl ester I_(b)-7 with hydrazine hydrate (80%) to obtaincompound I_(b)-15, and reacting compound I_(b)-7 with amine to obtainamides I_(b)-16 and I_(b)-18.

Path 10:

The tetrahydro-β-carboline alkaloid derivatives (I_(b)) described in thepresent invention may be prepared by the following method (Path 11):reacting acid I_(b)-1 with amine in presence of a condensation agent toobtain amides I_(b)-17, I_(b)-19-I_(b)-20.

Path 11:

The tetrahydro-β-carboline alkaloid derivatives (I_(c)) described in thepresent invention may be prepared by the following method (Path 12):reacting hydrazide compound I_(b)-15 with fatty aldehyde or aromaticaldehyde to obtain corresponding acylhydrazone type compoundI_(c)-1-I_(c)-29.

Path 12:

The tetrahydro-β-carboline alkaloid derivatives (I_(d)) described in thepresent invention may be prepared by the following method (Path 13):reacting hydrazide compound I_(b)-15 with acyl chloride to obtaincorresponding bishydrazide type compound I_(d)-1-I_(d)-7.

Path 13:

In the above general formulas,

R represents hydrogen, 1˜4 halogen atoms, 1˜4 nitro groups, 1˜4 cyanogroups, 1˜4 C1-C6 alkoxy groups, 1˜4 hydroxy groups, 1˜4 ester groups,1˜2OCH₂O, 1-2OCH₂CH₂O, 1˜4 C0-C10 amino groups, 1˜4 C1-C6 alkyl carbonylgroups, 1˜4 C1-C10 alkoxy carbonyl groups, 1˜4 C1-C10 alkyl aminocarbonyl groups, 1˜4 C1-C6 alkoxy carbonyloxy groups, 1˜4 C1-C6 alkylamino carbonyloxy groups, 1˜4 C1-C10 α-amino alkyl carbonyloxy groups:

R¹ respectively represents hydrogen, hydroxy, halogen atom, cyano group,ester group, amido group, C1-C10 hydrocarbyl, C1-C6 alkoxy, C1-C4 alkylcarbonyloxy, C1-C4 alkoxy carbonyloxy, C1-C10 nitrogen-containingheterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10sulfur-containing heterocyclic ring, as well as stereomers of theforegoing compounds;

R² respectively represents hydrogen, hydroxy, C1-C6 alkoxy, amino,C1-C10 amino, halogen atom, cyano group, aldehyde group, C1-C6 alkylcarbonyl, C1-C10 alkoxy carbonyl, C1-C10 alkyl amino carbonyl, C1-C6alkoxy carbonyloxy, C1-C6 alkyl amino carbonyloxy;

X respectively represents hydrogen, oxygen, sulfur, nitrogen, carbon;

R³ respectively represents hydrogen, hydroxy, halogen atom, cyano group,ester group, amido group, C1-C10 hydrocarbyl, C1-C6 alkoxy, C1-C4 alkylcarbonyloxy, C1-C4 alkoxy carbonyloxy, C1-C10 nitrogen-containingheterocyclic ring, C1-C10 oxygen-containing heterocyclic ring, C1-C10sulfur-containing heterocyclic ring;

R⁴ and R⁵ respectively represents hydrogen, C1-C10 hydrocarbyl, C1-C10nitrogen-containing heterocyclic ring, C1-C10 oxygen-containingheterocyclic ring, C1-C10 sulfur-containing heterocyclic ring; R⁴ and R⁵are C1-C10 aliphatic ring, C1-C10 unsaturated carbon ring, C1-C10nitrogen-containing heterocyclic ring, C1-C10 oxygen-containingheterocyclic ring, C1-10 sulfur-containing heterocyclic ring;

R⁶ respectively represents hydrogen, hydroxy, amino, C1-C10 hydrocarbyl,C1-C6 alkoxy, C1-C10 amino group, substituted phenyl ring, C1-C10nitrogen-containing heterocyclic ring, C1-C10 oxygen-containingheterocyclic ring, C1-C10 sulfur-containing heterocyclic ring.

The β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloidderivatives (I) described in the present invention are preferably thefollowing compounds:

-   (E)-3-(1-methyl-pyridino [3,4-b] indol-3)-acrylic acid (I_(a)-14);-   (E)-3-(1-(thiophene-2)-pyridino [3,4-b] indol-3)-acrylic acid    (I_(a)-15);-   (E)-3-(1-(pyridine-3)-pyridino [3,4-b] indol-3)-acrylic acid    (I_(a)-16);-   (1S, 3S)—N-butyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]    indol-3-formamide (I_(b)-16);-   (1S, 3S)—N-cyclohexyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]    indol-3-formamide (I_(b)-17);-   (1S, 3S)—N-(2-ethoxyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]    indol-3-formamide (I_(b)-18);-   (1S, 3S)—N-(dimethyl amino    methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]    indol-3-formamide (I_(b)-19);-   (1S,    3S)—N-((tetrahydrofuran-2)-methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino    [3,4-b] indol-3-formamide (I_(b)-20);-   (1S, 3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine-   (1S, 3S)—N′-(4-tert-butyl    benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-2);-   (1S, 3S)—N′-(4-dimethyl amino    benzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-3);-   (1S, 3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-4);-   (1S,    3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-5);-   (1S, 3S)—N′-(2,    4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-6);-   (1S,    3S)—N′-(4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-7);-   (1S,    3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-8);-   (1S, 3S)—N′-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-9);-   (1S,    3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-10);-   (1S,    3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-11);-   (1S, 3S)—N′-((benzo [d] [1, 3]    dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-12);-   (1S, 3S)—N-((2, 3-dihydrobenzo [b] [1, 4]    dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-13);-   (1S,    3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-14);-   (1S,    3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-15);-   (1S,    3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-16);-   (1S,    3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-17);-   (1S, 3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-18);-   (1S,    3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-19);-   (1S,    3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-20);-   (1S,    3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-21);-   (1S,    3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-22);-   (1S, 3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-23);-   (1S, 3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(c)-24);-   (1S, 3S)—N′-cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-25);-   (1S,    3S)—N-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-26);-   (1S, 3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-27);-   (1S,    3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-28);-   (1S, 3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(c)-29);-   N′—((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-tricarboxylate)benzo [d] [1,2,3]    thiadiazole-7-formylhydrazine (I_(d)-1);-   4-methyl-N′-((1S, 3S)methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-triformyl)-1,2,3-thiadiazole-5-formylhydrazine (I_(d)-2);-   (1S, 3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(d)-3);-   (1S, 3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(d)-4);-   (1S, 3S)—N′—N-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(d)-5);-   (1S, 3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]    indol-3-formylhydrazine (I_(d)-6);-   (1S, 3S)—N′-(cyclopentylformyl)-1-methyl-2,3,4,9-tetrahydropyridino    [3,4-b] indol-3-formylhydrazine (I_(d)-7).

The compounds shown in general formula (I) of the present invention haveexcellent activity against plant viruses, can satisfactorily inhibittobacco mosaic virus, chilli virus, rice virus, tomato virus, sweetpotato virus, potato virus and cucurbits virus and maize dwarf mosaicvirus, may effectively prevent and control virus diseases of tobacco,chilli, paddy, tomato, cucurbitaceous vegetable, grain, vegetable, beanand other crops, and is particularly applicable to the prevention andtreating of tobacco mosaic. β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloid derivatives shown in general formula (I)have very high in vitro activity against TMV and also show very good invivo activity against tobacco mosaic virus (TMV), and the in vivoactivity of some of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloid derivatives against tobacco mosaic virusis obviously better than that of commercial variety virazole.Particularly, the activity of compounds Harmalan, Tetrahydroharmane,Harmane, Tetrahydroharmine, I_(a)-1, I_(b)-13, I_(b)-15,I_(c)-1-I_(c)-9, I_(c)-12, I_(c)-19, I_(c)-20, I_(c)-24-I_(c)-26,I_(c)-28, I_(d)-1, I_(d)-6 and I_(d)-7 against tobacco mosaic virus atconcentration of 100 μg/mL is equivalent to the activity of commercialvariety ningnanmycin at concentration of 100 μg/mL. As far as we know,it is also the first time to report β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloid and their derivatives have activityagainst plant viruses.

The compounds shown in general formula (I) of the present invention canbe used as inhibitors of plant viruses directly, or used by adding anagriculturally acceptable vector, or used by forming interactivecompositions with other agents against plant viruses, such as:diazosulfide (BTH), tiadinil (TDL), 4-methyl-1,2,3-thiadiazole-5-formicacid (TDLA), DL-p-aminobutyric acid (BABA), virazole, ningnanmycin,phenanthroindolizidine alkaloid Antofine, linked triazole compoundsXY-13 and XY-30, virus A, salicylic acid, polyhydroxy dinaphthaldehydeand amino oligosaccharin. Some of these compositions show a synergisticeffect and some show an additive effect.

The compounds shown in general formula (I) of the present invention havethe activity of killing armyworms, cotton bollworms and corn borers aswell as culex pipiens.

The compounds shown in general formula (I) of the present invention showbactericidal activity against the following 14 kinds of pathogenicbacteria: cucumber fusarium wilt, Cercospora arachidicola, Macrophomakawatsukai, Alternaria solani, Fusarium graminearumt, potato lateblight, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani,Phytophthora capsici, Fusarium fujikuroi, Rhizoctonia cereali, Bipolariamaydis and Colletotrichum orbiculare.

The compounds shown in general formula (I) of the present invention canbe used as insecticides and bactericides directly, or used by adding anagriculturally acceptable vector, or used in combination with otherinsecticides, miticides and bactericides, such as: tebufenpyrad,chlorfenapyr, etoxazole and fenpyroximate etc. Some of thesecompositions show a synergistic effect and some show an additive effect.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The following embodiments and bioassay results are intended to furtherillustrate but not to limit the present invention.

Embodiment 1: Synthesis of Dihydro-β-Carboline Alkaloid Harmalan

Synthesis of Indol-3-Formaldehyde

Add 140 mL of DMF to a 500 mL single-necked flask, add 27 mL of POCl₃ at0° C., then add 50 mL of DMF solution containing 25 g (214 mmol) ofindole and stir them overnight. Add 50 mL of water and 150 mL of 20%NaOH aqueous solution in turn and heat and reflux them for 6 h. Pour thereaction solution into water and conduct suction filtration to obtain20.6 g of brown solid. The yield is 66% and the melting point is190-192° C. (literature value: 190-192° C.);

¹H NMR (400 MHz, CDCl₃)

δ 10.08 (s, 1H, CHO), 8.80 (s, 1H, NH), 8.32-8.34 (m, 1H, Ar—H), 7.86(d, ³J_(HH)=2.8 Hz, 1H, Ar—H), 7.44-7.62 (m, 1H, Ar—H), 7.31-7.36 (m,2H, Ar—H).

Synthesis of (E)-3-(Nitrovinyl) Indole

Add 20 g (138 mmol) of indol-3-formaldehyde, 5.3 g (69 mmol) of ammoniumacetate and 200 mL of nitromethane to a 500 mL single-necked flask, andheat and reflux them for 8 h. Add 200 mL of water and 150 mL of ethylacetate and separate the liquid. Wash the organic phase with water, dryit and evaporate the solvent under a reduced pressure. Usedichloromethane for column chromatography under normal pressure toobtain 19.1 g of yellow solid. The yield is 74% and the melting point is170-171° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H, NH), 8.30 (d, ³J_(HH)=13.6 Hz,1H, CH), 7.79-7.83 (m, 2H, CH and Ar—H), 7.69 (d, ³J_(HH)=2.8 Hz, 1H,Ar—H), 7.48-7.50 (m, 1H, Ar—H), 7.33-7.38 (m, 2H, Ar—H).

Synthesis of Tryptamine

Add 500 mL of tetrahydrofuran to a 1000 mL single-necked flask, and add11.4 g (300 mmol) of lithium aluminum hydride and 9.4 g (50 mmol) of(E)-3-(nitrovinyl) indole. Heat and reflux them for 7 h. Use water toquench lithium aluminum hydride not fully reacted. Conduct suctionfiltration, remove the solvent in the filtrate and add ethyl acetate andwater to separate liquid. Wash the organic phase with a saturated salinesolution, dry it with anhydrous sodium sulfate, remove solvent to obtaina red viscous substance, and dry it naturally to obtain 8.9 g of brownsolid. The yield is 89% and the melting point is 115-117° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H, NH), 7.62 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.36 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.20 (t, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.12 (t, ³J_(HH)=7.3 Hz, 1H, Ar—H), 7.02 (s, 1H, Ar—H), 3.04 (t,³J_(HH)=6.4 Hz, 2H, CH₂), 2.91 (t, ³J_(HH)=6.8 Hz, 2H, CH₂), 1.47 (s,2H, NH₂).

Synthesis of Harmalan

Add 0.5 g (3.13 mmol) of tryptamine, 40 mL of dichloromethane and 2 mLof triethylamine to a 100 mL single-necked flask. Add 5 mL ofdichloromethane solution containing 0.27 g (3.44 mmol) of acetylchlorideand react at room temperature for 5 h. Wash the reaction solution with asaturated sodium bicarbonate aqueous solution, dry it with anhydroussodium sulfate and remove the solvent. Add 20 mL of toluene, 20 mL ofchloroform and 3 mL of phosphorus oxychloride without the need ofpurification. Heat and reflux them for 7 h. Add sodium carbonate toregulate the reaction solution to be alkaline. Extract the reactionsolution with dichloromethane, and wash the organic phase with asaturated saline solution, dry it with anhydrous sodium sulfate andremove the solvent. Use dichloromethane/methanol (10:1) for columnchromatography under normal pressure to obtain 0.35 g of brownish yellowsolid. The yield is 60% and the melting point is 110-113° C.;

¹H NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H, NH), 7.60 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.48 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.31 (t, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.16 (t, ³J_(HH)=8.0 Hz, 1H, Ar—H), 3.88 (t, ³J_(HH)=8.4 Hz, 2H,CH₂), 2.95 (t, ³J_(HH)=8.8 Hz, 2H, CH₂), 2.53 (s, 3H, CH₃), HRMS (ESI)calcd for C₃₂H₁₃N₂(M+H)⁺ 185.1073. found 185.1077.

Embodiment 2: Synthesis of Tetrahydroharmane and Harmane

Synthesis of Tetrahydroharmane

Add 8.1 mL (43.75 mmol) of 40% acetaldehyde aqueous solution, 250 mL ofwater and 5 drops of concentrated sulfuric acid to a 500 mLsingle-necked flask. Stir them at room temperature for 0.5 h, add 3.50 g(21.88 mmol) of tryptamine and heat and reflux them for 7 h. Add NaOH toregulate pH value to around 10, extract the solution withdichloromethane, wash the organic phase with a saturated salinesolution, dry it with anhydrous sodium sulfate, remove the solvent, anduse dichloromethane/methanol (5:1) for column chromatography undernormal pressure to obtain 2.53 g of brown solid. The yield is 62% andthe melting point is 173-175° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 10.68 (s, 1H, NH), 7.35 (d, ³J_(HH)=8.0 Hz,1H, Ar—H), 7.27 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 6.98-7.02 (m, 1H, Ar—H),6.97-6.95 (m, 1H, Ar—H), 3.99-4.04 (m, 1H, CHNH), 3.33 (s, 1H, CHNH),3.14-3.19 (m, 1H, CH₂NH), 2.81-2.87 (m, 1H, CH₂NH), 2.51-2.62 (m, 2H,CH₂CH₂), 1.36 (d, ³J_(HH)=6.8 Hz, 3H, CH₂CH), HRMS (ESI) calcd forC₁₂H₁₂N₂(M+H)⁺ 187.1230. found 187.1231.

Synthesis of Harmane

Add 0.85 g (4.57 mmol) of tetrahydrocarboline, 0.53 g (4.57 mmol) ofmaleic acid, 120 mL of water and 0.85 g of Pd/C to a 250 mLsingle-necked flask. Heat and reflux them for 8 h, conduct suctionfiltration, wash with water and regulate pH value of the filtrate withNaOH to 9-10 to obtain a large amount of white solid. Conduct suctionfiltration to obtain 0.5 g of white solid. The yield is 60% and themelting point is 244-245° C.;

¹H NMR (400 Mhz, CDCl₃) δ 8.41 (s, 1H, NH), 8.37 (d, ³J_(HH)=5.2 Hz, 1H,Ar—H), 8.12 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.83 (d, ³J_(HH)=5.2 Hz, 1H,Ar—H), 7.52-7.57 (m, 2H, Ar—H), 7.26-7.32 (m, 1H, Ar—H), 2.84 (s, 3H,CH₃), HRMS (ESI) calcd for C₁₂H₁₁N₂(M+H)⁺ 183.0917. found 183.0915.

Embodiment 3: Synthesis of Tetrahydroharmine

Synthesis of Quaternary Ammonium Salt

Add 0.5 g (2.36 mmol) of harmine, 120 mL of ethyl acetate and 0.48 g(2.83 mmol) of benzyl bromide to a 250 mL single-necked flask. Heat andreflux them for 12 h. Conduct suction filtration to obtain 0.67 g oflight yellow solid. The yield is 74% and the melting point is above 300°C.;

¹H NMR (400 Mhz, d₆-DMSO) δ 12.78 (s, 1H, NH), 8.74 (d, ³J_(HH)=6.4 Hz,1H, Ar—H), 8.58 (d, ³J_(HH)=6.8 Hz, 1H, Ar—H), 8.37 (d, ³J_(HH)=8.8 Hz,1H, Ar—H), 7.35-7.44 (m, 3H, Ar—H), 7.23 (d, ³J_(HH)=7.2 Hz, 2H, Ar—H),7.12 (d, ³J_(HH)=1.0 Hz, 1H, Ar—H), 7.08 (dd, ³J_(HH)=8.8 Hz,³J_(HH)=1.0 Hz, 1H, Ar—H), 5.98 (s, 2H, CH₂), 3.95 (s, 3H, OCH₃), 2.98(s, 3H, CH₃).

Synthesis of N-Benzyl Tetrahydroharmine

Add 0.67 g (1.75 mmol) of quaternary ammonium salt and 150 mL ofmethanol to a 250 mL single-necked flask, and add 30 mL of methanolsolution containing 0.53 g (14.0 mmol) of sodium borohydride. Heat andreflux them for 15 h. Remove the solvent and add dichloromethane andwater to separate liquid. Wash the organic phase with a saturated salinesolution, dry it with anhydrous sodium sulfate, remove the solvent, anduse dichloromethane/methanol (20:1) for column chromatography undernormal pressure to obtain 0.47 g of brown solid. The yield is 88% andthe melting point is 147-149° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, 1H, NH), 7.50-7.52 (m, 2H, Ar—H),7.43-7.47 (m, 3H, Ar—H), 7.36-7.40 (m, 1H, Ar—H), 6.90 (dd, ³J_(HH)=8.8Hz, ³J_(HH)=2.4 Hz, 1H, Ar—H), 6.83 (d, ³J_(HH)=2.4 Hz, 1H, Ar—H), 3.97(d, ³J_(HH)=13.6 Hz, 1H, CH₂C₆H₅), 3.81 (q, ³J_(HH)=6.8 Hz, 1H, CHCH₃),3.77 (d, ²J_(HH)=13.6 Hz, 1H, CH₂C₆H₅), 3.22-3.29 (m, 1H, CH₂CH₂),2.85-2.95 (m, 2H, CH₂CH₂), 2.68-2.74 (m, 1H, CH₂CH₂), 1.61 (d,³J_(HH)=6.8 Hz, 1H, CHCH₃).

Synthesis of Tetrahydroharmine

Add 0.70 g (2.29 mmol) of N-benzyl-protected tetrahydroharmine, 120 mLof trifluoroethanol and 0.70 g of Pd/C to a 250 mL single-necked flask,input hydrogen and stir them overnight. Remove the solvent, and usedichloromethane/methanol (10:1) for column chromatography under normalpressure to obtain 0.37 g of light yellow viscous substance. The yieldis 80% and the melting point is 195-197° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, 1H, NH), 7.35 (d, ³J_(HH)=8.8 Hz, 1H,Ar—H), 6.85 (d, ³J_(HH)=2.0 Hz, 1H, Ar—H), 6.77 (dd, ³J_(HH)=8.4 Hz,³J_(HH)=2.4 Hz, 1H, Ar—H), 4.14-4.19 (m, 1H, CHCH₃), 3.84 (s, 3H, OCH₃),3.33-3.39 (m, 1H, CH₂CH₂), 3.01-3.07 (m, 1H, CH₂CH₂), 2.66-2.78 (m, 2H,CH₂CH₂), 1.65 (s, 1H, NH), 1.44 (d, ³J_(HH)=6.8 Hz, 3H, CH₃), HRMS (ESI)calcd for C₃₃H₃₇N₂O (M+H)⁺ 217.1335. found 217.1337.

Embodiment 4: Synthesis of Harmol

Add 0.5 g (2.36 mmol) of harmine, 18 mL of glacial acetic acid and 18 mLof 40% hydrobromic acid aqueous solution to a 100 mL single-neckedflask, and heat and reflux them for 10 h. Use saturated sodiumbicarbonate to regulate pH value to around 8 and generate precipitate.Conduct suction filtration to obtain 0.46 g of yellow green solid. Theyield is 98% and the melting point is above 300° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 11.24 (s, 1H, NH), 9.72 (s, 1H, OH), 8.11(d, ³J_(HH)=5.2 Hz, 1H, Ar—H), 7.94 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.75(d, ³J_(HH)=5.2 Hz, 1H, Ar—H), 6.90 (d, ⁴J_(HH)=1.2 Hz, 1H, Ar—H), 6.69(dd, ³J_(HH)=8.4 Hz, ⁴J_(HH)=1.6 Hz, 1H, Ar—H), 2.69 (s, 3H, CH₃), HRMS(ESI) calcd for C₁₂H₁₁N₂O (M+H)⁺ 199.0866. found 199.0867.

Embodiment 5: Synthesis of Bromo and Nitro-Substituted Harmane Synthesisof Bromo-Harmane (I_(a)-1 and I_(a)-2)

Add of 0.2 g (1.10 mmol) of harman and 10 mL of glacial acetic acid to a25 mL single-necked flask, add 0.2 g (1.10 mmol) of NB S, and react atroom temperature for 6 h. Remove the solvent, wash with saturated sodiumbicarbonate, extract with dichloromethane, dry the organic phase withanhydrous sodium sulfate, remove the solvent and usedichloromethane/methanol (40:1→20:1) in turn for column chromatographyunder normal pressure to obtain two kinds of white solid: solid I_(a)-10.05 g, yield 17%; ¹H NMR (400 MHz, CDCl₃) δ 8.36-8.49 (m, 2H, NH andAr—H), 8.04 (d, ³J_(HH)=6.4 Hz, 1H, Ar—H), 7.77-7.84 (m, 1H, Ar—H), 7.70(d, ³J_(HH)=6.4 Hz, 1H, Ar—H), 7.18 (t, ³J_(HH)=6.4 Hz, 1H, Ar—H), 2.88(s, 3H, CH₃). Solid I_(a)-2 0.24 g, yield 83%, melting point 256-257°C.;

¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H, NH), 8.39 (d, ³J_(HH)=5.6 Hz, 1H,Ar—H), 8.24 (d, ⁴J_(HH)=2.0 Hz, 1H, Ar—H), 7.78 (d, ³J_(HH)=5.6 Hz, 1H,Ar—H), 7.63 (dd, ³J_(HH)=8.4 Hz, ⁴J_(HH)=2.0 Hz, 1H, Ar—H), 7.42 (d,³J_(HH)=8.8 Hz, 1H, Ar—H), 2.83 (s, 3H, CH₃), HRMS (ESI) calcd forC₁₂H₁₃BrN₂(M+H)⁺ 261.0022. found 261.0026.

Synthesis of Nitro-Substituted Harmane (I_(c)-3 and I_(a)-4)

Add 0.4 g (2.20 mmol) of harman and 0.93 g (10.99 mmol) of sodiumnitrate to a 50 mL single-necked flask, add 20 mL of trifluoroaceticacid, and stir them at room temperature for 6 h. Add a saturated sodiumbicarbonate aqueous solution to the reaction solution to regulate pHvalue to 10-11 and generate yellow precipitate, and conduct suctionfiltration to obtain 0.06 g of yellow solid I_(a)-3. The yield is 12%and the melting point is 207-210° C.

¹H NMR (400 MHz, d₆-DMSO) δ 11.77 (s, 1H, NH), 8.77 (d, ³J_(HH)=7.6 Hz,Ar—H), 8.50 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 8.38 (d, ³J_(HH)=5.2 Hz, 1H,Ar—H), 8.11 (d, ³J_(HH)=5.2 Hz, 1H, Ar—H), 7.48 (t, ³J_(HH)=7.6 Hz, 1H,Ar—H), 2.92 (s, 3H, CH₃), HRMS (ESI) calcd for C₁₂H₁₉N₃O₃(M+H)⁺228.0768. found 228.0772, 0.36 g.

0.36 g of light yellow solid I_(a)-4. The yield is 12% and the meltingpoint is above 300° C.

¹H NMR (400 MHz, d₆-DMSO) δ 12.36 (s, 1H, NH), 9.30 (d, ⁴J_(HH)=2.0 Hz,1H, Ar—H), 8.41 (dd, ³J_(HH)=8.8 Hz, ³J_(HH)=3.0 Hz, 1H, Ar—H), 8.33 (d,³J_(HH)=5.6 Hz, 1H, Ar—H), 8.20 (d, ³J_(HH)=5.2 Hz, 1H, Ar—H), 7.73 (d,³J_(HH)=8.4 Hz, 1H, Ar—H), 2.79 (s, 3H, CH₃), HRMS (ESI) calcd forC₁₂H₁₀N₃O₂ (M+H)⁻ 228.0768. found 228.0767.

Embodiment 6: Synthesis of isopropylamino formate (1-methylpyridino[3,4-b] indol-7)-ester (I_(a)-5)

Add 0.5 g (2.53 mmol) of demethylated harmaline and 50 mL of DMF to a100 mL single-necked flask, add 1.5 mL of isopropyl isocyanate and 0.08g (0.758 mmol) of triethylamine, and stir them overnight. Add asaturated sodium chloride aqueous solution, extract with ethyl acetate,dry it with anhydrous sodium sulfate and remove the solvent. Usedichloromethane/methanol (20:1) for column chromatography under normalpressure to obtain 0.50 g of white solid. The yield is 70% and themelting point is above 300° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 11.58 (s, 1H, NH), 8.20 (d, ³J_(HH)=5.2 Hz,1H, Ar—H), 8.16 (d, ³J_(HH)=8.8 Hz, 1H, Ar—H), 7.90 (d, ³J_(HH)=5.2 Hz,1H, Ar—H), 7.76 (d, ³J_(HH)=8.0 Hz, 1H, NHCO), 7.27 (d, ⁴J_(HH)=1.6 Hz,1H, Ar—H), 6.95 (dd, ³J_(HH)=8.4 Hz, ⁴J_(HH)=2.0 Hz, 1H, Ar—H),3.65-3.73 (m, 1H, CH), 2.75 (s, 3H, CH₃), 1.16 (d, ³J_(HH)=3.4 Hz, 6H,(CH₃)₃CH), HRMS (ESI) calcd for C₁₆H₁₄N₂O₂ (M+H)⁺ 284.1394. found284.1399.

Embodiment 7: Synthesis of dimethylcarbamate (1-methylpyridino [3,4-b]indol-7)-ester (I_(a)-6)

Add 0.4 g (2.02 mmol) of demethylated harmaline, 150 mL oftetrahydrofuran, 0.31 g (3.03 mmol) of triethylamine and a catalyticamount of DMAP to a 250 mL single-necked flask, stir them at roomtemperature for 0.5 h, add 0.33 g (3.03 mmol) of acyl chloride and stirthem overnight. Remove the solvent, add dichloromethane and water toseparate liquid, wash the organic phase with a saturated salinesolution, dry it with anhydrous sodium sulfate, remove the solvent, anduse dichloromethane/methanol (10:11) for column chromatography undernormal pressure to obtain 0.48 g of white solid. The yield is 89% andthe melting point is 225-227° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 11.63 (s, 1H, NH), 8.20 (d, ³J_(HH)=5.2 Hz,1H, Ar—H), 8.17 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.91 (d, ³J_(HH)=5.2 Hz,1H, Ar—H), 7.30 (d, ³J_(HH)=2.0 Hz, 1H, Ar—H), 6.97 (dd, ³J_(HH)=8.4 Hz,⁴J_(HH)=2.0 Hz, 1H, Ar—H), 3.10 (s, 3H, CH₃), 2.94 (s, 3H, CH₃), 2.75(s, 3H, CH₃), HRMS (ESI) calcd for C₁₅H₁₆N₃O₂ (M+H)⁺ 270.1237. found270.1240.

Compounds I_(a)-7-I_(a)-8 are completed through repeating the foregoingsteps

Acetate (1-methylpyridino [3,4-b] indol-7)-ester (I_(a)-7)

White solid, yield 50%, melting point 237-240° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H, NH), 8.23 (d, ³J_(HH)=2.4 Hz, 1H,Ar—H), 7.78 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.70 (d, ³J_(HH)=2.0 Hz, 1H,Ar—H), 7.16 (s, 1H, Ar—H), 6.93 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 2.76 (s,3H, CH₃), 2.42 (s, 3H, CH₃CO), HRMS (ESI) calcd for C₁₄H₁₃N₂O₂ (M+H)⁺241.0972. found 241.0970.

Tert-valerate (1-methylpyridino [3,4-b] indol-7)-ester (I_(a)-8)

White solid, yield 85%, melting point 221-222° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H, NH), 8.30 (d, ³J_(HH)=5.2 Hz, 1H,Ar—H), 7.75 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.54 (d, ³J_(HH)=4.8 Hz, 1H,Ar—H), 7.09 (s, 1H, Ar—H), 6.86 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 2.73 (s,3H, CH₃), 1.45 (s, 9H, C(CH₃)₃), HRMS (ESI) calcd for C₁₇H₁₃N₂O₂ (M+H)⁺283.1441. found 283.1446.

Embodiment 8: Synthesis of(S)-3-methyl-2-carbobenzoxyaminobutyrate-(1-methylpyridino [3,4-b]indol-7-ester (I_(a)-9)

Add 0.80 g (3.03 mmol) of amino acid and 150 mL of dichloromethane to a250 mL single-necked flask, and add 0.41 g (4.04 mmol) of triethylamine,0.76 g (4.04 mmol) of EDCI (1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride) and 0.50 g (4.04 mmol) of DMAP(4-dimethylaminopyridine) and stir them overnight. Wash them with water,dry them with anhydrous sodium sulfate, remove the solvent, and usedichloromethane/methanol (20:1) for column chromatography under normalpressure to obtain 0.8 g of white solid. The yield is 92% and themelting point is 69-71° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H, NH), 8.54 (d, ³J_(HH)=5.2 Hz, 1H,Ar—H), 7.92 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.66 (d, ³J_(HH)=4.8 Hz, 1H,Ar—H), 7.35-7.38 (m, 5H, Ar—H), 7.19 (s, 1H, Ar—H), 6.94 (d, ³J_(HH)=8.4Hz, 1H, Ar—H), 5.39 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 5.17 (s, 2H, CH₂),4.54-4.66 (m, 1H, CHNH), 2.77 (s, 3H, CH₃), 2.38-2.50 (m, 1H, CH(CH₃)₂),1.14 (d, ³J_(HH)=6.8 Hz, 3H, CH(CH₃)₃), 1.09 (d, ³J_(HH)=6.8 Hz, 3H,CH(CH₃)₂), HRMS (ESI) calcd for C₂₃H₂₅N₃O₄(M+H)⁺ 432.1918. found432.1920.

Embodiment 9: (1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formic acid (I_(b)-1)

Add 20 g (98.0 mmol) of L-tryptophan, 500 mL of water, 2 mL ofconcentrated sulfuric acid and 20 mL of 40% acetaldehyde aqueoussolution to a 1000 mL single-necked flask, stir them at room temperatureovernight, use strong aqua to regulate pH value to 6-7, separate outwhite solid and conduct suction filtration to obtain 16.7 g of whitesolid. The yield is 74% and the melting point is 78-280° C.;

¹H NMR (400 MHz, d₆-DMSO) Γ 11.11 (s, 1H, COOH), 7.45 (d, ³J_(HH)=7.8Hz, 1H, Ar—H), 7.34 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.09 (t, ³J_(HH)=7.6Hz, 1H, Ar—H), 7.00 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.52 (q, ³J_(HH)=6.4Hz, 1H, CH), 3.61 (dd, ³J_(HH)=11.6 Hz, ³J_(HH)=4.4 Hz, 1H, CH), 3.16(dd, ²J_(HH)=16.0 Hz, ³J_(HH)=4.0 Hz, 1H, CH₂), 2.74-2.81 (m, 1H, CH₂),1.62 (d, ³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcd for C₂₃H₃₅N₂O₂(M+H)⁺ 231.1128. found 231.1132.

Compounds I_(b)-2 and I_(b)-3 are completed through repeating theforegoing steps

(1R,3R)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formic acid(I_(b)-2)

White solid, yield 76%, melting point 285-287° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 11.20 (s, 1H, COOH), 7.44 (d, ³J_(HH)=7.6Hz, 1H, Ar—H), 7.35 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.09 (t, ³J_(HH)=7.6Hz, 1H, Ar—H), 7.00 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 4.56 (q, ⁴J_(HH)=6.4Hz, 1H, CHCH₃), 3.64 (dd, ³J_(HH)=12.0 Hz, ³J_(HH)=4.8 Hz, 1H, CH), 3.18(dd, ³J_(HH)=16.0 Hz, ³J_(HH)=4.4 Hz, 1H, CH₃), 2.76-2.83 (m, 1H, CH₂),1.64 (d, ³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcd for C₁₃H₁₈N₂O₂(M+H)⁺ 231.1128. found 231.1132.

(1S, 3S)-1-ethyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-formic acid(I_(b)-3)

2.67 g of white solid, yield 44%, melting point 277-280° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 10.92 (s, 1H, COOH), 7.43 (d, ³J_(HH)=7.6Hz, 1H, Ar—H), 7.35 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.05-7.08 (m, 1H,Ar—H), 6.96-7.00 (m, 1H, Ar—H), 4.32-4.33 (m, H, CHNH), 3.54 (dd,³J_(HH)=11.6 Hz, ³J_(HH)=4.4 Hz, 1H, CHCO), 3.10 (dd, ³J_(HH)=15.6 Hz,³J_(HH)=4.0 Hz, 1H, CH₂), 2.70-2.78 (m, 1H, CH₂), 2.12-2.20 (m, 1H,CH₂CH₃), 1.83-1.90 (m, 1H, CH₂CH₃), 1.01 (t, ³J_(HH)=7.2 Hz, 3H,CH₂CH₃). HRMS (ESI) calcd for C₁₉H₁₇N₂O₂ (M+H)⁺ 245.1285. found245.1289.

Embodiment 10: Synthesis of 2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formic acid (I_(b)-4)

Add 10.00 g (49 mmol) of L-tryptophan, 1.96 g (49 mmol) of NaOH and 100mL of water to a 250 mL single-necked flask, and add 5 mL of 30%formaldehyde aqueous solution. Heat and reflux them for 3 h. Use 3Mdiluted hydrochloric acid to regulate pH value to around 5 and generateprecipitate, conduct suction filtration, wash the filter cakes withwater and dry them to obtain 8.32 g of white solid. The yield is 88% andthe melting point is 278-279° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 10.97 (s, 1H, COOH), 7.45 (d, ³J_(HH)=7.8Hz, 1H, Ar—H), 7.34 (d, ³J_(HH)=8.0 Hz, 1H Ar—H) 7.09 (t, ³J_(HH)=7.2Hz, 1H, Ar—H), 7.00 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.25 (d, ²J_(HH)=15.6Hz, 1H, NHCH₂), 4.18 (d, ³J_(HH)=15.6 Hz, 1H, NHCH₃), 3.62 (dd,³J_(HH)=10.4 Hz, ³J_(HH)=4.8 Hz, 1H, CH), 3.15 (dd, ³J_(HH)=16.4 Hz,³J_(HH)=4.8 Hz, 1H, CH₂), 2.83 (dd, ³J_(HH)=15.6 Hz, ³J_(HH)=10.8 Hz,1H, CH₃), HRMS (ESI) calcd for C₁₂H₁₃N₂O₂ (M+H)⁺ 217.0972. found217.0969.

Embodiment 11: Synthesis of (1S, 3S)-1-phenyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formic acid (I_(b)-5)

Add 2.5 g (12.3 mmol) of L-tryptophan, 50 mL of glacial acetic acid and1.5 g (13.5 mmol) of benzaldehyde to a 100 mL single-necked flask, heatand reflux them for 12 h, remove the solvent, use ammonium hydroxide toregulate pH value to 5-6 and generate precipitate, and conduct suctionfiltration to obtain 3.1 g of white solid. The yield is 86% and themelting point is 197-207° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 10.46 (s, 1H, COOH), 7.46 (d, ³J_(HH)=7.6Hz, 1H, Ar—H), 7.39-7.41 (m, 5H, Ar—H), 7.23 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.03 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 6.98 (t, ³J_(HH)=7.6 Hz, 1H,Ar—H), 5.43 (s, 1H, CH), 4.95 (br, 1H, NH), 3.80 (dd, ³J_(HH)=11.2 Hz,³J_(HH)=4.0 Hz, 1H, CH), 3.14 (dd, ³J_(HH)=18.4 Hz, ³J_(HH)=3.2 Hz, 1H,CH₃), 2.86-2.92 (m, 1H, CH₂), HRMS (ESI) calcd for C₁₈H₁₇H₂O₂ (M+H)⁺293.1285. found 293.1286.

Compound I_(b)-6 is completed through repeating the foregoing steps.

(1S, 3S)-1-(pyridine-3)-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formic acid (I_(b)-6)

Yellow solid, yield 87% and the melting point is 250-253° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H, COOH), 8.60 (d, ³J_(HH)=1.6Hz, 1H, Ar—H), 8.56 (dd, ³J_(HH)=4.8 Hz, ⁴J_(HH)=1.6 Hz, 1H, Ar—H), 7.70(dt, ³J_(HH)=8.0 Hz, ⁴J_(HH)=1.6 Hz, 1H, Ar—H), 7.47 (dd, ³J_(HH)=4.8Hz, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.20 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H),7.00-7.04 (m, 1H, Ar—H), 6.96-6.99 (m, 1H, Ar—H), 5.37 (s, 1H, CHAr),3.79 (dd, ³J_(HH)=11.2 Hz, ³J_(HH)=4.0 Hz, 1H, CHCOOH), 3.06-3.11 (m,1H, CH₂), 2.81-2.88 (m, 1H, CH₂). HRMS (ESI) calcd for C₁₇H₁₆N₃O₃(M+H)⁺294.1237. found 294.1237.

Embodiment 12: Synthesis of (1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-ethyl formate (I_(b)-13)

Add 16 g (69.0 mmol) of acid and 500 mL of anhydrous ethanol to a 1000mL single-necked flask, add 30 mL of thionyl chloride, and heat andreflux them for 5 h. Use a saturated sodium bicarbonate aqueous solutionto regulate pH value to 9 and generate precipitate, and conduct suctionfiltration to obtain 16.4 g of milky solid, The yield is 92% and themelting point is 136-137° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H, NH), 7.49 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.33 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.17 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.11 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.26-4.31 (m, 3H, CH andOCH₂), 3.81 (dd, ³J_(HH)=11.2 Hz, ³J_(HH)=4.4 Hz, 1H, CH), 3.13 (dd,²J_(HH)=15.2 Hz, ³J_(HH)=4.0 Hz, 1H, CH₂), 2.79-2.86 (m, 1H, CH₂), 1.52(d, ³J_(HH)=6.4 Hz, 3H, CH₂), 1.35 (t, ³J_(HH)=7.2 Hz, 3H, OCH₂CH₃),HRMS (ESI) calcd for C₁₈H₁₈N₂O₂ (M+H)⁺ 259.1441. found 259.1443.

Compounds I_(b)-7-I_(b)-12 are completed through repeating the foregoingsteps

(S)-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-ethyl formate (I_(b)-7)

Light yellow solid, yield 95%, melting point 50-53° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H, NH), 7.48 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.32 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.17 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.11 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.25-4.30 (m, 3H, CH andOCH₂), 3.83-3.86 (m, 4H, CH and OCH₃), 3.11-3.16 (m, 1H, CH₂), 2.80-2.87(m, 1H, CH₂), 1.51 (d, ³J_(HH)=6.8 Hz, 3H, CH₃), HRMS (ESI) calcd forC₁₆H₁₆N₂O₂ (M+H)⁺ 245.1285. found 245.1288.

(1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-butylformate (I_(b)-8)

Yellow oily substance, yield 68%;

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H, NH), 7.49 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.33 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.17 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.11 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.26-4.31 (m, 1H, CHCH₂),4.23 (t, ³J_(HH)=6.8 Hz, 2H, CH₂O), 3.82 (dd, ³J_(HH)=7.2 Hz,³J_(HH)=4.4 Hz, 1H, CHCO), 3.10-3.16 (m, 1H, CH₂), 2.78-2.85 (m, 1H,CH₂), 1.67-1.74 (m, 2H, OCH₂CH₂), 1.52 (d, ³J_(HH)=6.8 Hz, 3H, CHCH₃),1.41-1.48 (m, 2H, CH₂CH₃), 0.97 (t, ³J_(HH)=7.2 Hz, 3H, CH₂CH₃). HRMS(ESI) calcd for C₁₇H₂₃N₂O₂ (M+H)⁺ 287.1754. found 287.1759.

2,3,4,9-tetrahydropyridino [3,4-b] indol-3-ethyl formate (I_(b)-9)

Yellow solid, yield 90%, melting point 136-137° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H, NH), 7.49 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.31 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.16 (d, ³J_(HH)=7.2 Hz,⁴J_(HH)=4.8 Hz, 1H, Ar—H), 7.08-7.12 (m, 1H, Ar—H), 4.26 (q, ³J_(HH)=6.8Hz, 2H, OCH₃), 4.10-4.19 (m, 2H, CH₂NH), 3.79 (q, ³J_(HH)=4.8 Hz, 1H,CHCO), 3.14 (q, 1H, ³J_(HH)=7.2 Hz, 1H, CHCO₂Et), 3.14 (dd, ²J_(HH)=15.2Hz, ³J_(HH)=4.8 Hz, 1H, CH₂), 2.85-2.96 (d, ³J_(HH)=6.4 Hz, 1H, CH₂),1.93 (br, 1H, NH), 1.33 (t, ³J_(HH)=6.8 Hz, 3H, OCH₂CH₃), HRMS (ESI)calcd for C₁₇H₂₃N₂O₂ (M+H)⁺ 245.1285. found 245.1280.

(1S, 3S)-1-ethyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-ethylformate (I_(b)-10)

Yellow oily substance, yield 68%;

¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.33 (d,³J_(HH)=8.0 Hz, 1H, Ar—H), 7.14-7.18 (m, 1H, Ar—H), 7.09-7.13 (m, 1H,Ar—H), 4.26-4.32 (m, 2H, OCH₃), 4.15-4.18 (m, H, CHNH), 3.78 (dd,³J_(HH)=11.2 Hz, ³J_(HH)=4.0 Hz, 1H, CHCO), 3.11-3.16 (m, 1H, CH₂),2.77-2.84 (m, 1H, CH₂), 1.71-1.84 (m, 2H, CH₃CH₂), 1.35 (t, ³J_(HH)=7.2Hz, 3H, OCH₂CH₃), 1.90 (t, ³J_(HH)=7.2 Hz, 3H, CH₂CH₃), HRMS (ESI) calcdfor C₁₆H₂₁N₂O₂ (M+H)⁺ 273.1598. found 273.1602.

(1S, 3S)-1-(pyridine-3)-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-ethylformate (I_(b)-11)

White solid, yield 42%, melting point 239-240° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, ³J_(HH)=1.6 Hz, 1H, Ar—H), 8.55 (dd,³J_(HH)=4.4 Hz, ⁴J_(HH)=1.6 Hz, 1H, Ar—H), 7.94 (s, 1H, NH), 7.72 (dt,³J_(HH)=7.6 Hz, ³J_(HH)=1.6 Hz, 1H, Ar—H), 7.55-7.58 (m, 1H, Ar—H),7.24-7.29 (m, 2H, Ar—H), 7.11-7.19 (m, 2H, Ar—H), 5.31 (s, 1H, CHAr),4.28-4.31 (m, 2H, OCH₂CH₂), 3.97 (dd, ³J_(HH)=11.2 Hz, ³J_(HH)=4.0 Hz,1H, CHCOOMe), 3.26 (ddd, ³J_(HH)=14.8 Hz, ³J_(HH)=4.0 Hz, ⁴J_(HH)=1.6Hz, 1H, CH₂), 2.98-3.05 (m, 1H, CH₂), 1.35 (t, ³J_(HH)=6.8 Hz, 3H,OCH₂CH₃), HRMS (ESI) calcd for C₁₉H₂₀N₃O₂ (M+H)⁺ 322.1550. found322.1552.

(1R,3R)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-ethylformate (I_(b)-12)

Light yellow solid, yield 92%, melting point 121-122° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H, NH), 7.49 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.32 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.16 (d, ³J_(HH)=7.2 Hz,⁴J_(HH)=1.2 Hz, 1H, Ar—H), 7.11 (td, ³J_(HH)=7.2 Hz, ⁴J_(HH)=0.8 Hz, 1H,Ar—H), 4.26-4.31 (m, 3H, CH and OCH₂), 3.81 (dd, ³J_(HH)=11.2 Hz,³J_(HH)=4.4 Hz, 1H, CH), 3.13 (ddd, ³J_(HH)=15.2 Hz, ³J_(HH)=4.4 Hz,⁴J_(HH)=2.0 Hz, 1H, CH₂), 2.82 (ddd, ³J_(HH)=14.8 Hz, ³J_(HH)=11.2 Hz,⁴J_(HH)=2.4 Hz, 1H, CH₂), 1.51 (d, ³J_(HH)=6.8 Hz, 3H, CH₃), 1.35 (t,³J_(HH)=7.2 Hz, 3H, OCH₃CH₃), HRMS (ESI) calcd for C₁₃H₁₉N₂O₂ (M+H)⁺259.1441. found 259.1443.

Embodiment 13: 1-methyl-pyridino [3,4-b] indol-3-ethyl formate(I_(a)-10) and 1-methyl-pyridino [3,4-b] indol-3-formic acid (I_(a)-11)

1-methyl-pyridino [3,4-b] indol-3-ethyl formate (I_(a)-10)

Add 12.4 g (47.7 mmol) of tetrahydrocarboline, 3.1 g (95.4 mmol) ofelemental sulfur and 150 mL of xylol to a 250 mL single-necked flask,and heat and reflux them for 12 h. Cool them to separate out flesh pinksolid, and conduct suction filtration to obtain 8.4 g of flesh colorsolid. Yellow solid, yield 69%, melting point 217-219° C.;

¹H NMR (400 MHz, CDCl₃) δ 9.60 (s, 1H, NH), 8.79 (s, 1H, Ar—H), 8.18 (d,³J_(HH)=8.0 Hz, Ar—H), 7.54-7.60 (m, 2H, Ar—H), 7.32-7.36 (m, 1H, Ar—H),4.50 (d, ³J_(HH)=6.8 Hz, 2H, OCH₂), 2.79 (s, 3H, CH₃), 1.41 (t,³J_(HH)=7.2 Hz, 3H, OCH₂CH₃), HRMS (ESI) calcd for C₁₅H₁₉N₂O₂ (M+H)⁺227.0815. found 227.0811.

1-methyl-pyridino [3,4-b] indol-3-formic acid (I_(a)-11)

Add 2.00 g (7.87 mmol) of ester, 0.47 g (11.81 mmol) of NaOH and 60 mLof ethanol to a 100 mL single-necked flask, and heat and reflux them for6 h. Use 3M diluted hydrochloric acid to regulate pH value to 5-6 andgenerate precipitate, conduct suction filtration, wash filter cakes withwater and dry them to obtain 1.46 g of light yellow solid. The yield is82% and the melting point is above 300° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 12.04 (s, 1H, COOH), 8.77 (s, 1H, Ar—H),8.36 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.66 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H),7.60 (t, ³J_(HH)=7.0 Hz, 1H, Ar—H), 7.30 (d, ³J_(HH)=7.2 Hz, 1H, Ar—H),7.31 (d, ³J_(HH)=7.2 Hz, 1H, Ar—H), 2.82 (s, 3H, CH₃). HRMS (ESI) calcdfor C₁₃H₁₁N₂O₂ (M+H)⁺ 255.1128. found 255.1131.

Embodiment 14: Synthesis of (E)-3-(1-methyl-pyridino [3,4-b]indol-3)-acrylic acid (I_(a)-14)

(1-methyl-pyridino [3,4-b] indol-3)-methanol (I_(a)-12)

Add 2 g (7.4 mmol) of ester and 300 mL of tetrahydrofuran to a 500 mLsingle-necked flask, add 0.6 g (15.7 mmol) of lithium aluminum hydrideby batch, stir them at room temperature overnight, add water to quenchthe reaction, conduct suction filtration and remove the solvent of thefiltrate to obtain 1.58 g of yellow solid. The yield is 95% and themelting point is 195-197° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 11.46 (s, 1H, NH), 8.19 (d, ³J_(HH)=8.0 Hz,1H, Ar—H), 7.95 (s, 1H, Ar—H), 7.56 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H),7.49-7.53 (m, 1H, Ar—H), 7.18-7.22 (m, 1H, Ar—H), 5.30 (t, ³J_(HH)=6.0Hz, 1H, OH), 4.67 (d, ³J_(HH)=6.0 Hz, 2H, CH₂OH), 2.73 (s, 3H, CH₃).

1-methyl-pyridino [3,4-b] indol-3-formaldehyde (I_(a)-13)

Add 1.16 g (5.47 mmol) of alcohol, 3.04 g (10.93 mmol) of IBX and 60 mLof DMSO to a 100 mL single-necked flask, and stir them at roomtemperature overnight. Add 200 mL of water, use dichloromethane forextraction, wash the organic phase with a saturated saline solution, dryit with anhydrous sodium sulfate, remove the solvent, and usedichloromethane/methanol (10:1) for column chromatography under normalpressure to obtain 0.46 g of white solid. The yield is 40% and themelting point is 194-196° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 12.17 (s, 1H, NH), 10.07 (s, 1H, CHO), 8.68(s, 1H, Ar—H), 8.38 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.68 (d, ³J_(HH)=8.0Hz, 1H, Ar—H), 7.61 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.33 (t, ³J_(HH)=7.6Hz, 1H, Ar—H), 2.87 (s, 3H, CH₃).

(E)-3-(1-methyl-pyridino [3,4-b] indol-3)-acrylic acid (I_(a)-14)

Add 0.45 g (2.14 mmol) of aldehyde, 100 mL of pyridine and 3 drops ofpiperidine to a 250 mL single-necked flask, add 0.33 g (3.21 mmol) ofmalonic acid, and heat and react for 4 h. Use 3M diluted hydrochloricacid to regulate pH value of the water phase to 5-6, and conduct suctionfiltration to obtain 0.51 g of yellow solid. The yield is 94% and themelting point is 220-223° C.; ¹H NMR (400 MHz, d₆-DMSO) δ 12.22 (s, 1H,NH), 11.85 (s, 1H, COOH), 8.31 (s, 1H, Ar—H), 8.21 (d, ³J_(HH)=7.6 Hz,1H, Ar—H), 7.72 (d, ³J_(HH)=15.2 Hz, 1H, CHCH), 7.62 (d, ³J_(HH)=7.6 Hz,1H, Ar—H), 7.56 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.28 (t, ³J_(HH)=7.6 Hz,1H, Ar—H), 6.78 (d, ³J_(HH)=15.6 Hz, 1H, CHCH), 2.80 (s, 3H, CH₂); HRMS(ESI) calcd for C₁₅H₁₃N₂O₂ (M+H)⁺ 253.0972. found 253.0975.

Compounds I_(a)-15-I_(a)-16 are completed through repeating theforegoing steps

(E)-3-(1-(thiophene-2)-pyridino [3,4-b] indol-3)-acrylic acid (I_(a)-15)

Yellow solid, yield 85%, melting point 248-250° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 12.43 (s, 1H, NH), 12.10 (s, 1H, COOH), 8.47(s, 1H, Ar—H), 8.28 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 8.17 (d, ³J_(HH)=3.2Hz, 1H, Ar—H), 7.80 (d, ³J_(HH)=4.8 Hz, 1H, Ar—H), 7.77-7.80 (m, 2H,Ar—H), 7.62 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.33-7.38 (m, 2H, Ar—H andCHCH), 6.88 (d, ³J_(HH)=15.6 Hz, 1H, CHCH), 6.93 (d, ³J_(HH)=15.6 Hz,1H, CHCH); HRMS (ESI) calcd for C₁₈H₃₂N₂O₂ (M+H)⁺ 321.0692. found321.0694.

(E)-3-(1-(pyridine-3)-pyridino [3,4-b] indol-3)-acrylic acid (I_(a)-16)

Yellow solid, yield 50%, melting point>300° C.;

¹H NMR (400 MHz, d₆-DMSO) δ 12.43 (s, 1H, NH), 12.10 (s, 1H, COOH), 9.31(d, ³J_(HH)=1.6 Hz, 1H, Ar—H), 8.81 (dd, ³J_(HH)=4.8 Hz, 1H, Ar—H), 8.61(s, 1H, Ar—H), 8.56-8.59 (m, 1H, Ar—H), 8.31 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.84 (d, ³J_(HH)=15.6 Hz, 1H, CHCH), 7.76 (dd, ³J_(HH)=7.6 Hz,³J_(HH)=4.8 Hz, 1H, Ar—H), 7.70 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.62 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 7.35 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.93 (d,³J_(HH)=15.6 Hz, 1H, CHCH),

Embodiment 15: Synthesis of 1-methyl-4,9-dihydro-pyridino [3,4-b]indol-3)-ethyl formate (I_(b)-14)

L-tryptophan ethyl ester (6)

Add 0.50 g (24.50 mmol) of L-tryptophan and 150 mL of ethanol to a 250mL single-necked flask, add 15 mL of thionyl chloride, and heat andreflux them for 12 h. Remove the solvent to obtain 5.72 g of brownviscous substance, with a yield of 98%;

¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H, NH), 7.62 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.37 (d, ³J_(HH)=80 Hz, 1H, Ar—H), 7.20 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.13 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.08 (s, 1H, Ar—H), 4.14-4.19(m, 2H, OCH₂), 3.82 (dd, ³J_(HH)=7.6 Hz, ³J_(HH)=5.2 Hz, 1H, CH), 3.29(dd, ³J_(HH)=14.4 Hz, ³J_(HH)=5.2 Hz, 1H, CH₂), 3.05 (dd, ³J_(HH)=14.4Hz, ³J_(HH)=8.0 Hz, 1H, CH₂), 1.24 (t, ³J_(HH)=7.2 Hz, 3H, OCH₂CH₃).

1-methyl-4, 9-dihydro-pyridino [3,4-b] indol-3-ethyl formate (I_(b)-14)

Add 5.72 g (24.66 mmol) of tryptophan ethyl ester, 150 mL ofdichloromethane and 2.99 g (29.59 mmol) of triethylamine to a 250 mLsingle-necked flask, add 2.13 g (27.12 mmol) of acetylchloride and stirthem at room temperature for 5 h after dropwise addition. Use asaturated sodium bicarbonate to wash the reaction solution, extract withdichloromethane, wash the organic phase with a saturated salinesolution, dry it with anhydrous sodium sulfate and remove the solvent toobtain 5.96 g of brown viscous substance. Dissolve it in chloroform, add24 mL of POCl₃, and heat and reflux them for 5 h. Extract withdichloromethane, dry with anhydrous sodium sulfate, remove the solvent,and use dichloromethane/methanol (10:1) for column chromatography undernormal pressure to obtain 2.85 g of yellow solid. Yellow solid, yield45%, melting point 85-87° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H, NH), 7.61 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.41 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.30 (t, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.17 (t, ³J_(HH)=8.0 Hz, 1H, Ar—H), 4.43-4.48 (m, 1H, CHCO₂Et),4.31 (q, ³J_(HH)=7.2 Hz, OCH₂), 3.25 (dd, ³J_(HH)=16.4 Hz, ³J_(HH)=7.6Hz, 1H, CH₂CH), 3.08 (dd, ³J_(HH)=16.4 Hz, ³J_(HH)=14.8 Hz, 1H, CH₂CH),2.43 (d, ³J_(HH)=2.0 Hz, 3H, CH₃), 1.34 (t, ³J_(HH)=7.2 Hz, 3H,OCH₂CH₃), HRMS (ESI) calcd for C₁₅H₁₇N₂O₂ (M+H)⁺ 247.1285. found257.1287.

Embodiment 16: (1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(b)-15)

Add 1.00 g (4.1 mmol) of methyl ester, 50 mL of ethanol and 1.02 g (16.4mmol) of 80% hydrazine hydrate to a 100 mL single-necked flask, and heatand reflux them for 6 h. Remove the solvent, dissolve it in ethylacetate, wash it with a saturated saline solution, dry it with anhydroussodium sulfate, and remove the solvent to obtain 0.98 g of light yellowsolid, with a yield of 98%. White solid, yield 98% and melting point100-103° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H, NH), 7.90 (s, 1H, NHCO), 7.50 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.32 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.17 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 7.11 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.18-4.23(m, 1H, CHCH₃), 3.93 (br, 2H, NH₂), 3.65 (q, ³J_(HH)=8.4 Hz, 1H, CHCO),3.26-3.32 (m, 1H, CH₂), 2.71-2.78 (m, 1H, CH₂), 1.48 (d, ³J_(HH)=6.8 Hz,3H, CH₃), HRMS (ESI) calcd for C₁₃H₁₂N₄O (M+H)⁺ 245.1397. found245.1398.

Embodiment 17: Synthesis of (1S,3S)—N-butyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]indol-3-formamide (I_(b)-16)

Add 0.5 g (2.05 mmol) of methyl ester and 15 mL of n-butylamine to a 25mL single-necked flask, and stir them at room temperature overnight.Remove the solvent, add dichloromethane to dissolve it, wash it with asaturated saline solution, dry with anhydrous sodium sulfate and removethe solvent. Use dichloromethane/methanol (20:1) for columnchromatography under normal pressure to obtain 0.35 g of white solid.The yield is 60% and the melting point is 207-210° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H, NH), 7.49 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.31 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.15 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.10 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.17-4.22 (m, 1H, CHCH₃),3.58 (dd, ³J_(HH)=11.2 Hz, ³J_(HH)=4.4 Hz, 1H, CHCO), 3.28-3.38 (m, 3H,CHCH₂ and NHCH₂), 2.37-2.74 (m, 1H, CH₃), 1.51-1.59 (m, 2H, NHCH₂CH₂),1.49 (d, ³J_(HH)=10.8 Hz, 3H, CHCH₃), 1.34-1.43 (m, 2H, CH₂CH₃), 0.95(t, ³J_(HH)=7.22 Hz, 3H, CH₂CH₃); HRMS (ESI) calcd for C₁₃H₂₄N₂O (M+H)⁺286.1914. found 286.1919.

Compound I_(b)-18 is completed through repeating the foregoing steps

(1S, 3S)—N-(2-ethoxyl)-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]indol-3-formamide (I_(b)-18)

White solid, yield 64%, melting point 110-112° C.;

1H NMR (400 MHz, d₆-methanol) δ 7.39 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.29(d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.04-7.07 (m, 1H, Ar—H), 6.95-6.99 (m,1H, Ar—H), 4.18 (q, ³J_(HH)=6.8 Hz, 1H, CHCH₃), 3.67 (t, ³J_(HH)=6.4 Hz,2H, HOCH₂), 3.62 (dd, ³J_(HH)=11.2 Hz, ³J_(HH)=4.4 Hz, 1H, CHCO),3.38-3.42 (m, 3H, NHCH₂), 3.30-3.32 (m, 1H, ?), 3.02-3.08 (m, 1H,CH₂CHCO), 2.72-2.80 (m, 1H, CH₂CHCO), 1.52 (d, ³J_(HH)=6.8 Hz, 3H,CHCH₃); HRMS (ESI) calcd for C₁₃H₃₀N₂O₂ (M+H)⁺ 274.1550. found 274.1552.

Embodiment 18: Synthesis of (1S,3S)—N-cyclohexyl-1-methyl-2,3,4,9-tetrahydro-pyridino [3,4-b]indol-3-formamide (I_(b)-17)

White solid, yield 50%, melting point 231-233° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H, NH), 7.51 (d, ³J_(HH)=8.0 Hz, 1H,Ar—H), 7.32 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.14-7.18 (m, 1H, Ar—H),7.09-7.13 (m, 1H, Ar—H), 6.94 (d, ³J_(HH)=8.0 Hz, 1H, NHCO), 4.19-4.24(m, 1H, CHCH₃), 3.79-3.88 (m, 1H, NHCH), 3.57 (dd, ³J_(HH)=11.2 Hz,³J_(HH)=4.8 Hz, 1H, CHCO), 3.28-3.33 (m, 1H, COCHCH₂), 2.67-2.74 (m, 1H,COCHCH₂), 1.93-1.99 (m, 2H, CH₂), 1.73-1.73 (m, 2H, CH₃), 1.58-1.67 (m,2H, CH₂), 1.50 (d, ³J_(HH)=8.0 Hz, 3H, CHCH₃), 1.36-1.43 (m, 2H, CH₂),1.18-1.26 (m, 2H, CH₃), HRMS (ESI) calcd for C₁₉H₃₆N₉O (M+H)⁺ 312.2070.found 312.2076.

Compounds I_(b)-19, I_(b)-20 are completed through repeating theforegoing steps

(1S, 3S)—N-((dimethyl amino)methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino[3,4-b] indol-3-formamide (I_(b)-19)

White solid, yield 55%;

mp=110-112° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H, Ar—NH), 7.51 (d,³J_(HH)=8.0 Hz, 1H, Ar—H), 7.32 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.28 (m,1H, CONH), 7.16 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.11 (t, ³J_(HH)=7.2 Hz,1H, Ar—H), 4.22 (q, ³J_(HH)=6.8 Hz, 1H, CH), 3.61 (d, ³J_(HH)=4.4 Hz,³J_(HH)=11.2 Hz, 1H, CH), 3.51-3.36 (m, 2H, N—CH₂), 3.28 (ddd,³J_(HH)=2.0 Hz, ³J_(HH)=4.4 Hz, ²J_(HH)=16.0 Hz, 1H, CH₂), 2.74 (ddd,⁴J_(HH)=2.4 Hz, ³J_(HH)=11.2 Hz, ²J_(HH)=160 Hz, 1H, CH₂), 2.48 (t,³J_(HH)=6.4 Hz, 2H, CH₂), 2.27 (s, 6H, CH₃), 1.50 (d, ³J_(HH)=6.8 Hz,3H, CH₂); HRMS (ESI) calcd for C₁₇H₂₃N₄O (M+H)⁺ 301.2023. found301.2027.

(1S,3S)—N-((tetrahydrofuran-2)-methyl)-1-methyl-2,3,4,9-tetrahydro-pyridino[3,4-b] indol-3-formamide (I_(b)-20)

Yellow solid, yield 47%, melting point 95-97° C.;

¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H, NH), 7.55 (d, ³J_(HH)=7.6 Hz, 1H,Ar—H), 7.40-7.45 (m, 1H, NHCO), 7.36 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.20(t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.14 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 4.25(q, ³J_(HH)=6.8 Hz, 1H, CHCH₃), 4.04-4.10 (m, 1H, CHO), 3.90-3.95 (m,1H, CH₂O), 3.83 (dd, ³J_(HH)=7.2 Hz, ³J_(HH)=15.2 Hz, 1H, CHCO),3.63-3.70 (m, 2H, CH₂O and CH₂NH), 3.35 (dd, ³J_(HH)=16.0 Hz,³J_(HH)=4.4 Hz, 1H, CH₂CH), 3.18-3.30 (m, 1H, CH₂NH), 2.72-2.79 (m, 1H,CH₂CH), 2.02-2.98 (m, 1H, CH₂CH₂), 1.92-1.99 (m, 2H, CH₂CH₂), 1.59-1.65(m, 1H, CH₂CH₂), 1.53 (d, ³J_(HH)=6.8 Hz, 3H, CHCH₃), HRMS (ESI) calcdfor C₁₈H₂₃N₂O₁(M+H)⁺ 314.1863. found 314.1867.

Embodiment 19: (1S,3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-1)

Add 0.50 g (2.05 mmol) of hydrazide and 40 mL of toluene to a 100 mLsingle-necked flask, add 0.44 g (4.10 mmol) of benzaldehyde, and heatand reflux them for 5 h. Conduct suction filtration and wash withtoluene to obtain 0.50 g of yellow solid. The yield is 74% and themelting point is 200-204° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.48 and ³J_(HH)=7.6 Hz, 1H, Ph-H),7.49-7.42 (m, 2H, Ph-H), 7.42-7.33 (m, 2H, Ph-H and Ar—H), 7.31 and 7.30(d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.03 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.95and 6.92 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.48 and 3.61 (dd, ³J_(HH)=10.8Hz, 3.6 Hz, 1H, CH), 4.15 (d, ³J_(HH)=8.0 Hz, 1H, CH), 2.98-2.89 (m, 1H,CH₂), 2.71 and 2.62 (ddd, ³J_(HH)=2.0 Hz, ³J_(HH)=11.6 Hz, ³J_(HH)=14.4Hz, 1H, CH₂), 1.45 (d, ³J_(HH)=6.8 Hz, 3H, CH₃), HRMS (ESI) calcd forC₃₀H₂₁N₄O[M+H]⁺ 333.1710. found 333.1715.

Compounds I_(c)-2-I_(c)-29 are completed through repeating the foregoingsteps

(1S, 3S)—N′-(4-tert-butylbenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-2)

Yellow solid, yield 72%, melting point 139-143° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.47 and 11.32 (s, 1H, NH), 10.87 and 10.82(s, 1H, O═C—NH), 8.31 and 8.03 (s, 1H, N═CH), 7.88 and 7.70-7.27 (m, 6H,Ph-H and Ar—H), 7.04 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 6.96 (t, ³J_(HH)=7.2Hz, 1H, Ar—H), 4.48 and 3.62 (dd, ³J_(HH)=10.4 Hz, 7.2 Hz, 1H, CH),4.27-4.08 (m, 1H, CH), 3.02-2.88 (m, 1H, CH₂), 2.77-2.39 (m, 1H, CH₂),1.52-1.35 (m, 3H, CH₃), 1.30 and 1.24 (s, 9H, CH₃); HRMS (ESI) calcd forC₂₄H₂₉N₄O (M+H)⁺ 289.2336. found 389.2338.

(1S, 3S)—N′-(4-dimethyl aminobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-3)

Yellow solid, yield 73%, melting point 215-220° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.20 and 11.05 (s, 1H, NH), 10.84 and 10.80(s, 1H, O═C—NH), 8.16 and 7.92 (s, 1H, N═CH), 7.52 and 7.36 (d,³J_(HH)=7.6 Hz, 2H, Ph-H), 7.44-7.38 (m, 1H, Ar—H), 7.30 (d, ³J_(HH)=6.4Hz, 1H, Ar—H), 7.03 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 6.95 (t, ³J_(HH)=6.8Hz, 1H, Ar—H), 6.75 and 6.67 (d, ³J_(HH)=7.0 Hz, 2H, Ph-H), 4.44 and3.57 (d, ³J_(HH)=8.8 Hz, 1H, CH), 4.23-4.08 (m, 1H, CH), 3.07-2.86 (m,7H, N—CH₃ and CH₂), 2.74-2.56 (m, 1H, CH₂), 1.52-1.38 (m, 3H, CH₃); HRMS(ESI) calcd for C₃₂H₃₀N₅O [M+H]⁺ 376.2132. found 376.2137.

(1S, 3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-4)

Yellow solid, yield 74%, melting point 222-227° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.81 and 11.68 (s, 1H, NH), 10.87 and 10.82(s, 1H, O═C—NH), 8.46 and 8.17 (s, 1H, N═CH), 8.31 and 8.22 (d,³J_(HH)=8.4 Hz, 2H, Ph-H), 7.98 and 7.88 (d, ³J_(HH)=8.4 Hz, 2H, Ph-h),7.41 and 7.36 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.31 (d, ³J_(HH)=6.4 Hz,1H, Ar—H), 7.04 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.96 (t, ³J_(HH)=7.6 Hz,1H, Ar—H), 4.55 and 3.67 (d, ³J_(HH)=8.8 Hz, 1H, CH), 4.25-4.10 (m, 1H,CH), 2.86 (d, ³J_(HH)=13.6 Hz, 1H, CH₂), 2.79-2.60 (m, 1H, CH₂), 1.47(d, ³J_(HH)=6.4 Hz, 3H, CH₂); HRMS (ESI) calcd for C₂₀H₃₀N₃O[M+H]⁺378.1561. found 378.1563.

(1S, 3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-5)

Yellow solid, yield 81%, melting point 140-145° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.62 and 11.51 (s, 1H, NH), 10.91 and 10.85(s, 1H, O═C—CH), 8.35 and 8.07 (s, 1H, N═CH), 7.74 and 7.64 (d,³J_(HH)=7.2 Hz, 2H, Ph-H), 7.58-7.35 (m, 3H, Ph-H and Ar—H), 7.35-7.28(m, 1H, Ar—H), 7.10-7.00 (m, 1H, CH₂), 2.79-2.62 (m, 1H, CH₂), 1.54-1.39(m, 3H, CH₃); HRMS (ESI) calcd for C₂₁H₂₀N₂OCl[M+H]⁺ 367.1320. found367.1323.

(1S, 3S)—N′-(2,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-6)

yellow solid, yield 85%, melting point 211-213° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 and 11.77 (s, 1H, NH), 10.91 and 10.84(s, 1H, O═C—NH), 8.71 and 8.42 (s, 1H, N═CH), 8.00 and 7.85 (d,³J_(HH)=8.4 Hz, 1H, Ph-H), 7.73 and 7.71 (d, ³J_(HH)=2.0 Hz, 1H, Ph-H),7.53 and 7.43-7.35 (dd, ⁴J_(HH)=2.0 Hz, ³J_(HH)=8.4 Hz, 1H, Ph-H), 7.41and 7.37 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.32 and 7.31 (d, ³J_(HH)=8.0Hz, 1H, Ar—H), 7.04 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.96 and 6.94 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 4.65-4.56 and 3.66 (dd, ³J_(HH)=10.4 Hz, 6.3Hz, 1H, CH), 4.35-4.13 (m, 1H, CH), 3.06-2.91 (m, 1H, CH₂), 2.78-2.64(m, 1H, CH₂), 1.54-1.43 (m, 3H, CH₃); HRMS (ESI) calcd forC₂₀H₁₉N₄OCl₂[M+H]⁺ 401.0931. found 401.0929.

(1S,3S)—N′-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-7)

Yellow solid, yield 79%, melting point 189-193° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 and 11.67 (s, 1H, NH), 10.98 and 10.86(s, 1H, O═C—NH), 8.34 and 8.07 (s, 1H, N═CH), 7.94 and 7.88 (s, 1H,Ph-H), 7.72 and 7.64 (s, 2H, Ph-H), 7.41 and 7.39 (d, ³J_(HH)=8.4 Hz,1H, Ar—H), 7.33 and 7.31 (d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.06 and 7.04(t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.96 and 6.96 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 4.68 and 3.70 (dd, ³J_(HH)=10.4 Hz, 4.4 Hz, 1H, CH), 4.38 and4.19 (q, ³J_(HH)=6.4 Hz, 1H, CH), 3.06 and 2.98 (dd, ³J_(HH)=6.6 Hz,³J_(HH)=14.4 Hz, 1H, CH₂), 2.80-2.66 (m, 1H, CH₂), 1.53 and 1.48 (d,³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcd for C₂₀H₁₉N₄OCl₃[M+H]⁺401.0931. found 401.0934.

(1S, 3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-8)

Yellow solid, yield 69%, melting point 138-143° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.35 and 11.22 (s, 1H, NH), 10.84 and 10.81(s, 1H, O═C—NH), 8.27 and 8.00 (s, 1H, N═CH), 7.65 and 7.55 (d,³J_(HH)=8.0 Hz, 2H, Ph-H), 7.40 and 7.36 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H),7.30 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.08-6.89 (m, 4H, Ar—H and Ph-H),4.45 and 3.59 (d, ³J_(HH)=8.8 Hz, 1H, CH), 4.20-4.08 (m, 1H, CH), 3.81and 3.74 (s, 3H, O═CH₂), 2.93 (d, ²J_(HH)=14.4 Hz, 1H, CH₂), 2.76-2.56(m, 1H, CH₃), 1.45 (d, ⁵J_(HH)=6.0 Hz, 3H, CH₃), HRMS (ESI) calcd forC₂₁H₂₃N₄O₂[M+H]⁺ 363.1816. found 363.1819.

(1S, 3S)—N′-(3-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-9)

Yellow solid, yield 63%, melting point 186-190° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.54 and 11.39 (s, 1H, NH), 10.87 and 10.83(s, 1H, O═C—NH), 8.32 and 8.03 (s, 1H, N═CH), 7.45-7.11 (m, 5H, Ph-H andAr—H), 7.08-8.89 (m, 3H, Ar—H and Ph-H), 4.48 and 3.63 (d, ³J_(HH)=8.0Hz, 1H, CH), 4.25-4.10 (m, 1H, CH), 3.81 and 3.69 (s, 3H, O—CH₃),3.02-2.89 (m, 1H, CH₂), 2.77-2.60 (m, 1H, CH₂), 1.46 (d, ³J_(HH)=5.2 Hz,3H, CH₃); HRMS (ESI) calcd for C₂₃H₂₃N₃O₂[M+H]⁺ 363.1816. found363.1818.

(1S, 3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-10)

Yellow solid, yield 82%, melting point 180-183° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.52 and 11.46 (s, 1H, NH), 10.90 and 10.84(s, 1H, O═C—NH), 8.66 and 8.41 (s, 1H, N═CH), 7.84 and 7.68 (d,³J_(HH)=7.2 Hz, 1H, Ph-H), 7.41 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.37 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.31 (dd, ³J_(HH)=8.0 Hz, 1H, Ph-H),7.14-6.86 (m, 4H, Ph-H and Ar—H), 4.54 and 3.61 (dd, ³J_(HH)=10.0 Hz,2.8 Hz, 1H, CH), 4.30-4.10 (m, 1H, CH), 3.86 and 3.84 (s, 3H, O—CH₃),3.04-3.89 (m, 1H, CH₂), 2.77-2.60 (m, 1H, CH₂), 1.55-1.37 (m, 3H, CH₃);HRMS (ESI) calcd for C₂₁H₂₃N₆O₂[M+H]⁺ 363.1816. found 363.1823.

(1S,3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-11)

Light yellow solid, yield 91%, melting point 203-206° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.47 and 11.27 (s, 1H, NH), 10.89 and 10.83(s, 1H, O═C—NH), 8.25 and 7.99 (s, 1H, N═CH), 7.43-7.36 (m, 1H, Ar—H),7.34-7.27 and 7.22-7.15 (m, 3H, Ar—H and Ph-H), 7.07-6.91 (m, 3H, Ar—Hand Ph-H), 4.49 and 3.67-3.59 (dd, ³J_(HH)=11.2 Hz, 3.6 Hz, CH),4.33-4.11 (m, 1H, CH), 3.82 and 3.75 (s, 3H, O—CH₃), 3.81 and 3.64 (s,3H, O—CH₃), 3.03 and 2.94 (dd, ³J_(HH)=2.8 Hz, ³J_(HH)=14.8 Hz, 1H,CH₂), 2.76-2.65 (m, 1H, CH₂) 1.48 and 1.46 (d, ³J_(HH)=6.8 Hz, 3H, CH₃);HRMS (ESI) calcd for C₂₂H₂₃N₄O₄[M+H]⁺ 393.1921. found 393.1918.

(1S, 3S)—N′-((benzo [d] [1,3]dioxymethylene-5)-methylene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-12)

Yellow solid, yield 83%, melting point 199-203° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.41 and 11.26 (s, 1H, NH), 10.86 and 10.81(s, 1H, O═C—NH), 8.24 and 7.96 (s, 1H, N═CH), 7.40 and 7.36 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.31 and 7.30 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H),7.28 and 7.17 (s, 1H, Ph-H), 7.15 and 7.09 (d, ³J_(HH)=8.0 Hz, 1H,Ph-H), 7.06-6.96 (m, 2H, Ar—H and Ph-H), 6.94 (t, ³J_(HH)=7.6 Hz, 1H,Ar—H), 6.10 (s, 1H, O—CH₂), 6.02 (d, ²J_(HH)=4.8 Hz, 1H, O—CH₂), 4.49and 3.60 (dd, ³J_(HH)=10.8 Hz, 3.6 Hz, CH), 4.22 and 4.13 (m, 1H, CH),2.99-2.87 (m, 1H, CH₂), 2.75-2.87 (m, 1H, CH₂), 1.45 (d, ³J_(HH)=6.4 Hz,3H, CH₃); HRMS (ESI) calcd for C₂₁H₂₃N₄O₃[M+H]⁺ 377.1608. found377.1615.

(1S, 3S)—N′-(2, 3-dihydrobenzo [b] [1,4]dioxin-6-methylene)-1-methyl)-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-13)

Light yellow solid, yield 81%, melting point 204-207° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.44 and 11.26 (s, 1H, NH), 10.89 and 10.82(s, 1H, O═C—NH), 8.21 and 7.94 (s, 1H, c═CH), 7.40 and 7.36 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.32 and 7.30 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H),7.20 and 7.10 (s, 1H, Ph-H), 7.19 and 7.09 (d, ³J_(HH)=7.6 Hz, 1H,Ph-H), 7.07-7.01 (m, 1H, Ar—H), 6.99-6.83 (m, 2H, Ar—H and Ph-H), 4.51and 3.61 (dd, ³J_(HH)=10.8 Hz, 3.6 Hz, 1H, CH), 4.35-4.09 (m, 5H, CH andO—CH₂—CH₂—O), 3.03-2.89 (m, 1H, CH₂), 2.76-2.60 (m, 1H, CH₂), 1.53-1.43(m, 3H, CH₃), HRMS (ESI) calcd for C₂₂H₂₃N₄O₂[M+H]⁺ 391.1765. found391.1763.

(1S,3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-14)

Yellow solid, yield 70%, melting point 275-278° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.46 and 11.35 (s, 1H, NH), 10.85 and 10.81(s, 1H, O═C—NH), 9.98 (s, 1H, OH), 8.42 and 8.16 (s, 1H, N═CH), 7.99 and7.91 (s, 1H, Naphthalene-H), 7.85 (d, ³J_(HH)=9.2 Hz, 1H,Nahphthalene-H), 7.80 and 7.61 (d, ³J_(HH)=8.8 Hz, 1H, Naphthalene-H),7.74 and 7.70 (d, ³J_(HH)=8.8 Hz, 1H, Naphpthalene-H), 7.42 and 7.37 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.16 and 7.08 (s, 1H, Naphthalene-H),7.15-7.09 (m, 1H, Naphthalene-H), 7.04 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H),7.00-6.90 (m, 1H, Ar—H), 4.52 and 3.63 (d, ³J_(HH)=8.4 Hz, 1H, CH),4.25-4.10 (m, 1H, CH), 3.02-2.90 (m, 1H, CH₂), 2.73 and 2.65 (t,³J_(HH)=12.8 Hz, 1H, CH₂), 1.47 (d, ³J_(HH)=6.0 Hz, 3H, CH₃); HRMS (ESI)calcd for C₂₄H₂₃N₄O₂[M+H]⁺ 399.1816. found 399.1822.

(1S, 3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-15)

Yellow solid, yield 79%, melting point 235-239° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.84 and 11.69 (s, 1H, NH), 10.90 and 10.84(s, 1H, O═C—NH), 8.65 and 8.57 (d, ³J_(HH)=5.6 Hz, 2H, Py-H), 8.35 and8.05 (s, 1H, N═CH), 7.65 and 7.57 (d, ³J_(HH)=5.6 Hz, 2H, Py-H), 7.41and 7.37 (d, ³J_(HH)=7.6 Hz, 1H, Ph-H), 7.34-7.29 (m, 1H, Ar—H), 7.04(t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 6.95 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 4.58and 3.67 (dd, ³J_(HH)=10.8 Hz, 3.6 Hz, 1H, CH), 4.26 and 4.16 (q,³J_(HH)=6.4 Hz, 1H, CH), 3.05-2.91 (m, 1H, CH₂), 2.80-2.62 (m, 1H, CH₂),1.48 (d, ³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcd for C₂₅H₂₀N₅O[M+H]⁺334.1662. found 334.1663.

(1S, 3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-16)

Yellow solid, yield 72%, melting point 205-209° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.74 and 11.58 (s, 1H, NH), 10.91 and 10.84(s, 1H, O═C—NH), 8.84 and 8.79 (s, 1H, Py-H), 8.62 and 8.55 (d,³J_(HH)=4.0 Hz, 1H, Py-H), 8.41 and 8.12 (s, 1H, N═CH), 8.12 and 8.03(d, ³J_(HH)=4.0 Hz, 1H, Py-H), 7.49 and 7.44-7.35 (m, 2H, Py-H andAr—H), 7.33 and 7.31 (d, ³J_(HH)=7.6 Hz, 1H, Ph-H), 7.04 (t, ³J_(HH)=7.6Hz, 1H, Ar—H), 6.96 (t, ³J_(HH)=7.6 Hz, 1H, Ar—H), 4.59 and 3.66 (dd,³J_(HH)=10.8 Hz, 3.6 Hz, 1H, CH), 4.32 and 4.12 (m, 1H, CH), 3.85-2.92(m, 1H, CH₃), 2.78-2.63 (m, 1H, CH₃), 1.53-1.39 (m, 3H, CH₃); HRMS (ESI)calcd for C₂₉H₂₈N₉O[M+H]⁺ 334.1662. found 334.1664.

(1S, 3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-17)

Yellow solid, yield 72%, melting point 245-249° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.69 and 11.65 (s, 1H, NH), 10.85 and 10.82(s, 1H, O—C—NH), 8.62 and 8.57 (d, ³J_(HH)=4.8 Hz, 1H, Py-H), 8.36 and8.10 (s, 1H, N═CH), 7.95 and 7.80 (d, ³J_(HH)=8.0 Hz, 1H, Py-H), 7.88and 7.75 (td, ³J_(HH)=1.2 Hz, ³J_(HH)=7.6 Hz, 1H, Py-H), 7.44-7.33 (m,2H, Py-H and Ar—H), 7.31 and 7.30 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.03(t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.95 and 6.92 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 4.50 and 3.63 (dd, ³J_(HH)=10.8 Hz, 4.0 Hz, CH), 4.16 (q,³J_(HH)=8.9 Hz, 1H, CH), 2.94 (ddd, ³J_(HH)=1.6 Hz, ³J_(HH)=4.4 Hz,²J_(HH)=14.8 Hz, 1H, CH₂), 2.72 and 2.63 (ddd, ⁴J_(HH)=2.0 Hz,⁴J_(HH)=10.8 Hz, ²J_(HH)=14.8 Hz, 1H, CH₂), 1.46 and 1.45 (d,³J_(HH)=6.8 Hz, 3H, CH₃); HRMS (ESI) calcd for C₁₉H₂₀N₂O[M+H]⁺ 334.1662.found 334.1666.

(1S, 3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-18)

Yellow solid, yield 62%, melting point 144-148° C.;

¹H NMR (400 MHz, CDCl₃) δ 10.33 and 10.20 (s, 1H, NH), 8.26 and 8.11 (s,1H, O═C—NH), 8.04 and 7.72 (s, 1H, N═CH), 7.51-7.38 (m, 2H, Ar—H andfuran-H), 7.34 and 7.31 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.14 (t,³J_(HH)=6.8 Hz, 1H, Ar—H), 7.08 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.77 and6.62 (s, 1H, furan-H), 6.45 and 6.42 (s, 1H, furan-H), 4.65 and 3.69 (d,³J_(HH)=7.6 Hz, 1H, CH), 4.32-4.11 (m, 1H, CH), 3.30 and 3.19 (d,³J_(HH)=13.6 Hz, 1H, CH₂), 2.79 (t, ³J_(HH)=13.2 Hz, 1H, CH₂), 1.97 (br,1H, NH), 1.52 and 1.46 (d, ³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcdfor C₁₈H₁₉N₄O₂[M+H]⁺ 323.1503. found 323.1505.

(1S, 3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine

Red solid, yield 75%, melting point 207-209° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.52 and 11.31 (s, 1H, NH), 11.16 and 11.05(s, 1H, Pyrrole-NH), 10.83 and 10.80 (s, 1H, O═C—NH), 8.15 and 7.88 (s,1H, N═CH), 7.45-7.35 (m, 1H, Ar—H), 7.30 (d, ³J_(HH)=7.2 Hz, 1H, Ar—H),7.03 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.95 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H),6.90 and 6.83 (s, 1H, Pyrrole-H), 6.45 and 6.39 (s, 1H, Pyrrole-H), 6.13and 6.08 (s, 1H, Pyrrole-H), 4.60 and 3.58 (d, ³J_(HH)=8.8 Hz, 1H, CH),4.24-4.08 (m, 1H, CH), 2.98-2.88 (m, 1H, CH₂), 2.70-2.59 (m, 1H, CH₂),1.50-1.45 (m, 3H, CH₃); HRMS (ESI) calcd for C₁₈H₂₀N₄O[M+H]⁺ 322.1662.found 322.1668.

(1S, 3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine

Yellow solid, yield 76%, melting point 139-141° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.55 and 11.39 (s, 1H, NH), 10.90 and 10.83(s, 1H, O═C—NH), 8.56 and 8.24 (s, 1H, N═CH), 7.67 and 7.54 (d,³J_(HH)=4.8 Hz, 1H, Thiophene-H), 7.47-7.35 (m, 2H, Thiophene-H andAr—H), 7.35-7.28 (m, 1H, Ar—H), 7.14 and 7.09 (t, ³J_(HH)=4.4 Hz, 1H,Thiophene-H), 7.04 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.00-6.90 (m, 1H,Ar—H), 4.38 and 3.62 (dd, ³J_(HH)=8.8 Hz, 4.0 Hz, 1H, CH), 4.29-4.10 (m,1H, CH), 3.04-2.89 (m, 1H, CH₂), 2.77-2.61 (m, 1H, CH₂), 1.54-1.38 (m,3H, CH₃); HRMS (ESI) calcd for C₁₈H₁₉N₁OS [M+H]⁺ 339.1274. found339.1278.

(1S, 3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine

Green solid, yield 81%, melting point 188-190° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 14.10, 13.33, 12.81 and 12.57 (s, 1H,Imidazole-NH), 12.93 and 11.47 (s, 1H, NH), 10.84 and 10.81 (s, 1H,O═C—NH), 8.45, 8.26, 7.95 and 7.44 (s, 1H, N═CH), 7.42-6.88 (m, 6H, Ar—Hand Imidazole-H), 4.65, 4.50, 3.69 and 3.63 (m, 1H, CH), 4.37 and 4.17(m, 1H, CH), 3.03 and 2.95 (d, ³J_(HH)=14.0 Hz, 1H, CH₂), 2.78-2.56 (m1H, CH₃), 1.52-1.42 (m, 3H, CH₃); HRMS (ESI) calcd for C₃₇H₁₉N₆O[M+H]⁺323.1615. found 323.1620.

(1S, 3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-22)

Yellow solid, yield 61%, melting point 145-148° C.;

¹H NMR (400 MHz, CDCl₃) δ 10.10 and 9.63 (s, 1H, NH), 8.23 and 8.15 (s,1H, O═C—NH), 7.72 and 7.37 (d, ³J_(HH)=8.4 Hz, 1H, N═CH), 4.57-4.48 and3.70-3.58 (m, 1H, CH), 4.31-4.06 (m, 1H, CH), 3.27 and 3.12 (d,³J_(HH)=14.4 Hz, 1H, CH₂), 2.85-2.66 (m, 1H, CH₂), 2.09 (br, 1H, NH),1.92-1.75 (m, 3H, CH₃), 1.50 and 1.43 (d, ³J_(HH)=5.6 Hz, 3H, CH₃); HRMS(ESI) calcd for C₁₈H₂₀N₅O[M+H]⁺ 297.1710. found 297.1714.

(1S, 3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-23)

Yellow solid 0.52 g, yield 71%, melting point 113-117° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 and 10.97 (s, 1H, NH), 10.82 and 10.80(s, 1H, O═C—NH), 7.59 and 7.42-7.33 (m, 3H, N═CH and Ar—H), 7.30 (d,³J_(HH)=7.6 Hz, 1H, Ph-H), 7.03 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 6.95 (t,³J_(HH)=6.8 Hz, 1H, Ar—H), 4.28 and 3.51 (d, ³J_(HH)=9.6 Hz, 1H, CH),4.19-4.04 (m, 1H, CH), 2.89 (d, ³J_(HH)=14.0 Hz, 1H, CH₂), 2.67 and 2.57(t, ²J_(HH)=12.8 Hz, 1H, CH₂), 2.25-2.10 (m, 2H, CH₂), 1.55-1.40 (m, 3H,CH₃ and CH₂), 0.92 and 0.86 (t, ³J_(HH)=6.8 Hz, 3H, CH₃); HRMS (ESI)calcd for C₁₇H₂₃N₄O[M+H]⁺ 299.1866. found 299.1870.

(1S, 3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-24)

Yellow solid, yield 78%, melting point 68-71° C.;

¹H NMR (400 MHz, CDCl₃) δ 9.94 and 9.02 (s, 1H, NH), 7.90 and 7.50 (s,1H, N═CH), 7.50 and 7.46 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.34 and 7.32(d, ³J_(HH)=8.4 Hz, 1H, Ar—H), 7.17 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.11(t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.53 and 3.76 (dd, ³J_(HH)=11.2 Hz, 4.4Hz, 1H, CH), 4.33-4.17 (m, 1H, CH), 3.37 and 3.13 (dd, ³J_(HH)=2.8 Hz,³J_(HH)=14.4 Hz, 1H, CH₂), 2.83-2.72 (m, 1H, CH₂), 2.38 and 2.22 (q,³J_(HH)=7.2 Hz, 2H, CH₂), 1.96 (br, 1H, NH), 1.58-1.43 (m, 3H, CH₃ andCH₃), 1.42-1.18 (m, 9H, CH₂), 0.95-0.81 (m, 3H, CH₃); HRMS (ESI) calcdfor C₂₁H₃₅N₄O[M+H]⁺ 355.2493. found 355.2492.

(1S, 3S)—N′-(cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-25)

Yellow solid, yield 92%, melting point 123-126° C.;

¹H NMR (400 MHz, CDCl₃) δ 9.88 and 9.21 (s, 1H, NH), 7.98 and 7.96 (s,1H, N═CH), 7.49 and 7.47 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.38-7.29 and7.05 (m, 2H, Ar—H and O═C—NH), 7.16 and 7.16 (t, ³J_(HH)=7.2 Hz, 1H,Ar—H), 7.10 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.52 and 3.66 (dd,²J_(HH)=10.8 Hz, 4.4 Hz, 1H, CH), 4.28 and 4.18 (q, ³J_(HH)=6.8 Hz, 1H,CH), 3.35 and 3.12 (dd, ³J_(HH)=2.8 Hz, ³J_(HH)=15.6 Hz, 1H, CH₂),2.85-2.72 (m, 1H, CH₂), 2.47-2.35 and 2.23-2.13 (m, 1H, CH), 1.94 (br,1H, NH), 1.87-1.58 (m, 4H, CH₃), 1.53 and 1.48 (d, ³J_(HH)=10.8 Hz, 3H,CH₃), 1.38-1.11 (m, 6H, CH₂), 0.95-0.81 (m, 3H, CH₃); HRMS (ESI) calcdfor C₂₀H₂₇N₄O[M+H]⁺ 339.2180. found 339.2179.

(1S, 3S)—N′-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-26)

Yellow solid, yield 95%, melting point 140-141° C.;

¹H NMR (400 MHz, CDCl₃) δ 9.93 and 9.39 (s, 1H, NH), 8.13 and 8.09 (s,1H, N═CH), 7.53-7.02 (m, 4H, Ar—H), 4.51 and 3.67 (d, ³J_(HH)=8.4 Hz,1H, CH), 4.37-4.16 (m, 1H, CH), 3.33 and 3.13 (d, ³J_(HH)=14.4 Hz, 1H,CH₂), 2.79 (t, ²J_(HH)=13.2 Hz, 1H, CH₂), 2.09 (br, 1H, NH), 1.58-1.41(m, 3H, CH₃), 1.15 and 1.66 (s, 9H, CH₃); HRMS (ESI) calcd forC₁₈H₂₅N₄O[M+H]⁺ 313.2023. found 313.2028.

(1S, 3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-27)

Light yellow solid, yield 56%, melting point 221-224° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.84 and 10.81 (s, 1H, N—H), 10.69 and10.48 (s, 1H, O═C—NH), 7.89-7.77 and 7.76-7.67 (m, 2H, Ph-H), 7.48-7.27(m, 5H, Ph-H and Ar—H), 7.08-6.88 (m, 2H, Ar—H), 4.53 and 3.78 (dd,³J_(HH)=10.8 Hz, 3.6 Hz, 1H, CH), 4.23-4.11 (m, 1H, CH), 3.03-2.93 (m,1H, CH₂), 2.76-2.59 (m, 1H, CH₂), 3.31 and 3.30 (s, 3H, CH₃), 1.46 (d,³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcd for C₂₃H₂₂N₄O[M+H]⁺ 347.1867.found 347.1872.

(1S, 3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-28)

Yellow solid, yield 63%, melting point 103-107° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.80 and 10.79 (s, 1H, N—H), 10.18 and10.02 (s, 1H, O═C—NH), 7.40 and 7.35 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.29(d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.03 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.95and 6.93 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 4.26 and 3.65 (dd, ³J_(HH)=10.8Hz, 4.0 Hz, 1H, CH), 4.16-4.07 (m, 1H, CH), 2.94 (dd, ³J_(HH)=2.8 Hz,³J_(HH)=14.8 Hz, 1H, CH₂), 2.70-2.53 (m, 1H, CH₂), 1.87 and 1.85 (s, 3H,CH₃), 1.43 (d, ³J_(HH)=6.4 Hz, 3H, CH₃), 1.12 and 1.04 (s, 9H, CH₃);HRMS (ESI) calcd for C₂₆H₂₃N₂O[M+H]⁺ 327.2180. found 327.2186.

(1S, 3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-29)

Yellow solid, yield 60%, melting point 131-135° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 and 10.78 (s, 1H, NH), 10.39 and 10.24(s, 1H, O═C—NH), 7.39 and 7.36 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.29 (d,³J_(HH)=7.6 Hz, 1H, Ar—H), 7.02 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.94 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 4.36 and 3.62 (dd, ³J_(HH)=10.0 Hz, 3.6 Hz,1H, CH), 4.18-4.04 (m, 1H, CH), 2.94-2.84 (m, 1H, CH₂), 2.69-2.58 (m,1H, CH₂), 2.40-2.12 (m, 4H, CH₂), 1.71-1.51 (m, 6H, CH₂), 1.42 (d,³J_(HH)=6.0 Hz, 3H, CH₃); HRMS (ESI) calcd for C₁₉H₂₅N₄O[M+H]⁺ 325.2023.found 325.2023.

Embodiment 20: N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-tricarboxylate)benzo [d] [1, 2, 3] thiadiazole-7-formylhydrazine(I_(d)-1)

Add 0.40 g (1.64 mmol) of hydrazide and 40 mL of tetrahydrofuran to a100 mL single-necked flask, add 0.22 g (2.17 mmol) of NEt₃, add atetrahydrofuran solution containing acyl chloride (1.64 mmol), stir themat room temperature overnight after dropwise addition and remove thesolvent to obtain 0.48 g of green solid. The yield is 72% and themelting point is 180-183° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 11.22 (br, 1H,O═C—NH), 10.91 (s, 1H, NH), 10.37 (br, 1H, O═C‥NH), 9.00 (d, ³J_(HH)=8.0Hz, 1H, Ph-H), 8.62 (d, ³J_(HH)=7.2 Hz, 1H, Ph-H), 7.99 (t, ³J_(HH)=7.6Hz, 1H, Ph-H), 7.44 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.33 (d, ³J_(HH)=8.0Hz, 1H, Ar—H), 7.06 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.99 (t, ³J_(HH)=7.2Hz, 1H, Ar—H), 4.40-4.20 (m, 1H, CH), 3.97-3.76 (m, 1H, CH), 3.11-2.99(m, 1H, CH₂), 2.85-2.73 (m, 1H, CH₂), 1.50 (d, ³J_(HH)=6.0 Hz, 3H, CH₃);HRMS (ESI) calcd for C₂₀H₃₃N₆O₂S[M+H]⁺ 407.1285. found 407.1281.

Compounds I_(d)-2-I_(d)-7 are completed through repeating the foregoingsteps

4-methyl-N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-triformyl)-1,2,3-thiadiazole-5-formylhydrazine (I_(d)-2)

Green solid, yield 56%, melting point 145-148° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H, NH), 10.29 (br, 1H, O═C—NH),7.40 (d, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.31 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H),7.04 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H), 6.97 (t, ³J_(HH)=6.8 Hz, 1H, Ar—H),4.25-4.11 (m, 1H, CH), 3.78-3.62 (m, 1H, CH), 3.03-2.92 (m, 1H, CH₂),2.85 (s, 3H, CH₃), 2.78-2.64 (m, 1H, CH₂), 1.46 (d, ³J_(HH)=5.2 Hz, 3H,CH₃); HRMS (ESI) calcd for C₁₃H₁₅N₆O₂S[M+H]⁺ 371.1285. found 371.1287.

(1S, 3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-3)

Brown solid, yield 23%, melting point 243-245° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (s, 2H, NH and O═C—NH), 10.14 (br, 1H,O═C—NH), 8.78 (d, ³J_(HH)=4.0 Hz, 2H, Py-H), 7.81 (d, ³J_(HH)=4.0 Hz,2H, Py-H), 7.39 (d, ³J_(HH)=7.2 Hz, 1H, Ar—H), 7.30 (d, ³J_(HH)=7.6 Hz,1H, Ar—H), 7.04 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.96 (t, ³J_(HH)=7.2 Hz,1H, Ar—H), 4.18-4.08 (m, 1H, CH), 3.68-3.59 (m, 1H, CH), 2.98-2.88 (m,1H, CH₃), 2.76-2.64 (m, 1H, CH₃), 1.44 (d, ³J_(HH)=6.4 Hz, 3H, CH₃);HRMS (ESI) calcd for C₁₅H₂₀N₅O₃[M+H]⁺ 350.1612. found 350.1606.

(1S, 3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-4)

yellow solid, yield 93%, melting point 140-143° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, NH), 10.47 (br, 1H, O═C—NH),10.02 (br, 1H, and O═C—NH), 7.92 (d, ³J_(HH)=7.2 Hz, 2H, Ph-H), 7.60 (t,³J_(HH)=7.2 Hz, 1H, Ph-H), 7.52 (t, ³J_(HH)=7.2 Hz, 2H, Ph-H), 7.40 (d,³J_(HH)=7.2 Hz, 1H, Ar—H), 7.31 (d, ³J_(HH)=8.0 Hz, 1H, Ar—H), 7.04 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 6.97 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 4.20-4.11(m, 1H, CH), 3.66 (dd, ³J_(HH)=10.0 Hz, 3.2 Hz, 1H, CH), 2.95 (dd,³J_(HH)=2.8 Hz, ³J_(HH)=14.4 Hz, 1H, CH₂), 2.75-2.65 (m, 1H, CH₂), 1.45(d, ³J_(HH)=6.8 Hz, 3H, CH₃); HRMS (ESI) calcd for C₃₀H₂₁N₄O₂[M+H]⁺349.1659. found 349.1665.

(1S, 3S)—N′—N-Hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-5)

Light yellow solid, yield 78%, melting point 97-100° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H, NH), 9.87 (s, 1H, O═C—NH),9.81 (br, 1H, O═C—NH), 7.37 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.29 (d,³J_(HH)=8.0 Hz, 1H, Ar—H), 7.03 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.95 (t,³J_(HH)=7.2 Hz, 1H, Ar—H), 4.15-4.03 (m, 1H, CH), 3.55 (dd, ³J_(HH)=10.4Hz, 3.6 Hz, 1H, CH), 2.87 (dd, ³J_(HH)=2.4 Hz, ²J_(HH)=14.8 Hz, 1H,CH₂), 2.62 (ddd, ³J_(HH)=2.0 Hz, ³J_(HH)=10.8 Hz, ²J_(HH)=14.8 Hz, 1H,CH₂), 2.15 (t, ³J_(HH)=7.2 Hz, 2H, CH₂), 1.60-1.48 (m, 2H, CH₂), 1.42(d, ³J_(HH)=6.8 Hz, 3H, CH₃), 1.24-1.21 (m, 4H, CH₂CH₂), 6.88 (t,³J_(HH)=6.8 Hz, 2H, CH₂); HRMS (ESI) calcd for C₁₉H₂₇N₈O₂[M+H]⁺343.2129. found 343.2132.

(1S, 3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-6)

Yellow solid, yield 93%, melting point 124-126° C.;

¹H NMR (400 MHz, CDCl₃) δ 8.83 (br, 1H, O═C—NH), 8.34 (s, 1H, O═C—NH),7.25 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.15 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H),7.00 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.93 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H),3.95-3.81 (m, 1H, CH), 3.49 (dd, ³J_(HH)=10.8 Hz, 1H, CH), 3.05-2.97 (m,1H, CH₂), 2.63-2.50 (m, 1H, CH₂), 1.30-1.07 (m, 12H, CH₃); HRMS (ESI)calcd for C₁₈H₂₅N₆O₂[M+H]⁺ 329.1972. found 429.1975.

(1S, 3S)—N′-(cyclopentyl formyl)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(d)-7)

White solid, yield 80%, melting point 141-144° C.;

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H, NH), 9.94-9.74 (m, 2H,O═C—NH), 7.37 (d, ³J_(HH)=7.6 Hz, 1H, Ar—H), 7.30 (d, ³J_(HH)=8.0 Hz,1H, Ar—H), 7.03 (t, ³J_(HH)=7.2 Hz, 1H, Ar—H), 6.96 (t, ³J_(HH)=7.2 Hz,1H, Ar—H), 4.19-4.06 (m, 1H, CH), 3.66-3.54 (m, 1H, CH), 2.96-2.84 (m,1H, CH₂), 2.72-2.57 (m, 2H, CH₂ and cyclopentyl-CH), 1.85-1.48 (m, 8H,cyclopentyl-CH₂), 1.43 (d, ³J_(HH)=6.4 Hz, 3H, CH₃); HRMS (ESI) calcdfor C₁₉H₂₅N₈O₂[M+H]⁺ 341.1972. found 341.1968.

Embodiment 21: Determination of Activity Against Tobacco Mosaic Virus,and the Determination Procedure is as Follows

1. Virus Purification and Concentration Determination:

Virus purification and concentration determination are executed byreferring to the SOP for tobacco mosaic virus formulated by BioassayLaboratory of the Research Institute of Elmento-organic Chemistry atNankai University. After the crude extract of virus undergoescentrifugal treatment of polyethylene glycol twice, its concentration isdetermined. It is kept at 4° C. for future use.

2. Preparation of a Compound Solution:

After weighing, DMF is added to dissolve the crude drug and obtain a1×10⁵ m/mL mother solution. Then it is diluted with a 1%0 Tween 80aqueous solution to the needed concentration; water is added toningnanmycin formulation for dilution.

3. In Vitro Effect:

Mechanically inoculate the leaves of Nicotiana tabacum L.cv.Xanthi NN atan appropriate age and wash them with water (virus concentration is 10m/mL). Cut them off after water drains, halves each leaf along themidrib, soak the left half leaf and the right half leaf in 1%0 Tweenwater and drug respectively, take them out 30 min later, and culturethem at appropriate illumination and temperature in a moist state. Use 3leaves each time and repeat the test 3 times. Record the number ofnecrotic lesions and calculate the preventive effect 3d later.

4. In Vivo Protective Effect:

Select evenly growing Nicotiana tabacum L.cv.Xanthi NN in 3-5-leafstage, spray drug to the whole plants, repeat the treatment 3 times, anduse 1%0 Tween 80 aqueous solution as control. Sprinkle emery (50 mesh)on leaf surface 24 h later, dip virus solution by a writing brush, smearthe solution on the whole leaves along the direction of branch veinstwice, hold up the leaves with palm under them (virus concentration is10 μg/mL) and wash the leaves with running water after inoculation.Record the number of necrotic lesions and calculate the preventiveeffect 3d later.

5. In Vivo Therapeutic Effect:

Select evenly growing Nicotiana tabacum L.cv.Xanthi NN in 3-5-leaftstage, inoculate the virus to whole leaves by a writing brush (virusconcentration is 10 μg/mL), and wash the leaves with running water afterinoculation. Spray drug to the whole plants after the water on leafsurface drains, repeat the treatment for 3 times, and use 1%0 Tween 80aqueous solution as control. Record the number of necrotic lesions andcalculate the preventive effect 3d later.

6. In Vivo Inactivation:

Select evenly growing Nicotiana tabacum L.cv.Xanthi NN in 3-5-leaftstage, mix the drug with virus juice in an equal volume forinactivation, mechanically inoculate it 30 min later (virusconcentration is 20 μg/mL), wash with running water after inoculation,repeat the treatment for 3 times, and use 1%0 Tween 80 aqueous solutionas control. Record the number of necrotic lesions and calculate theresult 3d later.Inhibition rate (%)=[(number of necrotic lesions in the controlgroup-number of necrotic lesions in the treatment group)/number ofnecrotic lesions in the control group]×100%

TABLE 1 Test results of anti-TMV activity of some of β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloids and theirderivatives (I_(a), I_(b), I_(c) and I_(d)): Relative inhibition rate(%) Treatment In vivo dose In vitro inacti- In vivo In vivo No. (μg/mL)activity vation therapy protection Harmalan 500 58.6 62.3 55.1 60.3 10030 32.7 34.8 35.6 Tetrahydroharmane 500 63.7 64.2 57.2 59.5 100 28.423.5 20.4 24.6 Harmane 500 54.3 50.6 50 57.8 100 16.4 17.7 23.7 26.9Tetrahydroharmine 500 58.2 59.8 55.5 54.6 100 28.7 26.4 27.3 24.2Harmine 500 44.6 40.5 38.6 42.4 100 20 11.4 15.8 16.3 Harmol 500 32.635.1 30 36.7 100 0 0 0 9.5 I_(a)-1 500 44.5 46.3 47.4 51.2 100 18.2 14.919.3 20.4 I_(a)-3 500 15.7 21.5 18.5 26.1 100 0 0 0 0 I_(a)-4 500 3036.4 33.3 30.1 100 0 10.5 0 5.8 I_(a)-5 500 31.3 29.5 32.7 40.3 100 0 00 5.8 I_(a)-6 500 12.6 12 15.6 18.7 100 0 0 0 0 I_(a)-7 500 30 20.3 24.127.2 100 0 0 0 0 I_(a)-8 500 0 15.3 0 14.4 100 0 0 0 0 I_(a)-9 500 20.713.6 12.5 19.6 100 0 0 0 0 I_(a)-10 500 33.3 26.3 28.8 23.7 100 0 0 0 0I_(a)-11 500 32.5 27.3 29.6 21.4 100 0 0 0 0 I_(a)-14 500 25.8 18.4 21.528.4 100 0 0 0 0 I_(a)-15 500 40.2 39.6 36.2 35.1 100 0 13.5 10 10.2I_(a)-16 500 17.8 26.5 20.2 21.3 100 0 0 0 0 I_(b)-1 500 41.6 35.5 40.441.3 100 18.9 13.5 15.8 20 I_(b)-2 500 25 28.6 31.5 29.7 100 0 0 0 0I_(b)-5 500 19.7 27.6 24.3 32.3 100 0 0 0 0 I_(b)-6 500 25 17.5 21.424.8 100 0 0 0 0 I_(b)-7 500 26.9 36.5 30.7 40.1 100 12.3 19.3 15.9 16.2I_(b)-8 500 48.2 51.3 42.2 43.2 100 13.4 20.3 17.1 17.6 I_(b)-9 500 44.541 42.7 40.4 100 12.8 16.9 14.3 17.2 I_(b)-10 500 34.1 46.4 38.1 36.6100 0 12.6 11.4 10.7 I_(b)-11 500 40.9 37 38.9 36.7 100 0 13.1 18 14.3I_(b)-12 500 40 35.8 38.6 41.9 100 12.6 16.7 12.9 17 I_(b)-13 500 46.550.4 43.9 47.9 100 21.8 25.7 17.5 18.6 I_(b)-14 500 42.6 35.7 45.8 47100 11.1 0 15.9 21.4 I_(b)-15 500 50 46 48.2 49.6 100 21.4 16.5 20.323.4 I_(b)-16 500 38.4 44 44.9 42.1 100 0 13.5 21.1 15.8 I_(b)-17 50038.8 43.3 44.6 37.1 100 0 12.3 15.1 14.2 I_(b)-18 500 37.6 41.5 40 41100 5.4 10 18.6 12.1 I_(b)-19 500 26.6 18.5 20.9 24.7 100 0 0 0 0I_(b)-20 500 37.5 39.1 34.2 29.6 100 0 9.8 0 0 I_(c)-1 500 55.8 56.351.5 53.2 100 28.4 19.6 16 21.8 I_(c)-2 500 52.4 50.3 47 53.8 100 17.613.3 18.2 21.7 I_(c)-3 500 56.8 64.5 60.4 62.4 100 20.4 25 23.1 18.9I_(c)-4 500 62.8 58.3 57.1 61.5 100 19.6 27.4 20.8 21.4 I_(c)-5 500 67.370.4 71.5 64.2 100 30.8 35.9 29.2 34.1 I_(c)-6 500 56.8 66.7 60.4 57.2100 20.1 28.5 31.5 18.6 I_(c)-7 500 50.7 55.2 48.9 48.1 100 15.1 20.423.5 14.8 I_(c)-8 500 62.5 69.1 66.4 70 100 28.7 30.4 34.8 31.8 I_(c)-9500 53.2 59.2 54 54.7 100 13.2 22.1 16.5 20.6 I_(c)-10 500 38.5 43.236.4 34.8 100 0 0 10.9 0 I_(c)-11 500 37.2 47.1 40.5 42.3 100 7.8 20.316.2 11 I_(c)-12 500 72.6 74.5 69 68.1 100 29.1 33.6 30.2 35.8 I_(c)-13500 46.5 43.6 48.1 46 100 19.8 15.2 18.6 10.3 I_(c)-14 500 40.9 45.643.9 47.8 100 0 16.9 8.2 0 I_(c)-15 500 36.6 43.4 39.6 37.5 100 0 8.812.9 0 I_(c)-16 500 33.3 41 36.9 33.6 100 0 11.2 5.7 0 I_(c)-17 500 32.738.9 36.8 31.4 100 0 9.2 0 0 I_(c)-18 500 48.8 54.6 44.2 47.5 100 15.418.2 9.3 11.5 I_(c)-19 500 49.5 61.3 63.4 54.7 100 8.8 20.2 27.8 30I_(c)-20 500 58.5 59.1 52.3 61.3 100 23 29.6 25.1 31.8 I_(c)-21 500 42.449.6 45.3 48.1 100 0 21.3 12.6 18.5 I_(c)-22 500 35.2 47 33.2 37.1 100 08.5 0 6.7 I_(c)-23 500 32.6 47.1 41.3 40.5 100 7.8 13.4 10.4 11.3I_(c)-24 500 61.3 73.4 70.9 59.6 100 23.2 32.8 31.7 27.3 I_(c)-25 50059.6 75.8 62.8 69.2 100 31.2 36.3 30.4 25.7 I_(c)-26 500 64.4 63.7 68.266.8 100 27.5 28.9 36.8 33.4 I_(c)-27 500 30.2 39.5 34.8 37.2 100 9.213.6 11.1 7.9 I_(c)-28 500 58.1 59.7 55.4 56.8 100 25.6 21.3 16.7 18.9I_(c)-29 500 43.4 33 41.9 46.2 100 8.6 12.8 10.9 14.3 I_(d)-1 500 52.144.1 54.5 58.3 100 22.6 16.2 26.8 29.9 I_(d)-2 500 41.2 42.9 48.8 51.3100 13.5 9.8 19.1 16 I_(d)-3 500 39.2 45.3 45 42.1 100 6.4 17.9 11.614.2 I_(d)-4 500 36.9 37.5 34.2 40 100 0 0 0 12.1 I_(d)-5 500 32.1 31.527.3 30.9 100 0 0 0 0 I_(d)-6 500 45.7 44 42.1 47.5 100 8.9 12.8 14.216.9 I_(d)-7 500 47.2 42.4 51.4 53.9 100 22.2 20.3 18.6 26.6 NK-007 50065.4 65.2 67.2 67.9 100 38.7 33.9 34.9 36.2 Virazole 500 39.5 36.3 35.437.6 100 15.3 12.9 11.9 16.2 Ningnanmycin 500 73.3 68 54.2 65.4 100 26.838.4 20 23.1

Table 1 indicates most of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloids and their derivatives (I_(a), I_(b),I_(c) and I_(d)) show very high in vitro anti-TMV activity, most of thecompounds show very good in vivo activity against tobacco mosaic virus(TMV), and most of alkaloid and acylhydrazone compounds obviouslyoutperform commercial variety virazole in anti-TMV in vivo activity.Particularly, the anti-TMV activity of compounds Harmalan,Tetrahydroharmane, Harmane, Tetrahydroharmine, I_(a)-1, I_(b)-8,I_(b)-15, I_(c)-1-I_(c)-9, I_(c)-12, I_(c)-19, I_(c)-20,I_(c)-24-I_(c)-26, I_(c)-28, I_(d)-1, I_(d)-6 and I_(d)-7 at 100 μg/mLis equivalent to the activity of commercial variety ningnanmycin at 100μg/mL, and they have great development value.

Embodiment 22: Determination of Fungicidal Activity, and theDetermination Procedure is as Follows

In vitro test method (Alternaria solani is taken for example.Alternatively, other fungi may be used): Inoculate Alternaria solani toPDA culture medium, culture it for 7 days, prepare Φ4 cm bacteria platesfrom colony edge by a puncher, inoculate 50 m/mL and drug-free PDAculture media, culture them for 4 days, measure colony diameter, comparewith the control group and calculate the inhibition percentage of thedrug.

TABLE 2 Test results of bactericidal activity of some of β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloids and theirderivatives (I_(a), I_(b), I_(c) and I_(d)): Bactericidal activity(%)/50 mg/kg Cucumber fusarium Cercospora Macrophoma Alternaria FusariumFusarium Sclerotinia Phytophthora Rhizoctonia Bipolaria Colletotrichumpotato Rhizoctonia Botrytis No. wilt arachidicola kawatsukai solanigraminearumt fujikuroi scleotiorum capsici cereali maydis orbicularelate blight solani cinerea Harmalan 23.1 76.9 2.4 26.3 21.4 28.6 19.60.0 55.3 27.3 25.0 31.8 19.7 15.2 Tetrahydr 19.2 61.5 26.2 26.3 14.314.3 9.8 0.0 42.1 18.2 32.1 18.2 52.6 12.1 Harmane 19.2 92.3 61.9 68.423.8 35.7 33.3 15.6 42.1 36.4 46.4 9.1 26.3 12.1 Tetrahydr 19.2 76.914.3 21.1 11.9 14.3 19.6 9.4 34.2 27.3 25.0 22.7 26.3 27.3 Harmine 28.657.1 35.3 83.3 92.9 57.1 48.0 60.6 71.9 31.6 57.1 35.0 21.4 59.1 Harmol26.9 46.2 23.8 26.3 23.8 28.6 5.9 25.0 42.1 31.8 46.4 22.7 50.0 9.1I_(a)-1 65.4 84.6 61.9 73.7 76.2 64.3 41.2 93.8 68.4 86.4 92.9 45.5 96.145.5 I_(a)-3 23.8 7.1 35.3 33.3 50.0 42.9 56.0 36.4 59.4 31.6 23.8 25.010.7 54.6 I_(a)-4 38.5 53.9 35.7 15.8 42.9 21.4 29.4 9.4 50.0 36.4 42.927.3 42.1 18.2 I_(a)-5 34.6 53.9 2.4 21.1 23.8 14.3 9.8 25.0 36.8 22.739.3 18.2 6.6 0.0 I_(a)-6 23.1 53.9 26.2 15.8 38.1 21.4 7.8 9.4 36.827.3 35.7 9.1 46.1 12.1 I_(a)-7 14.3 35.7 5.9 33.3 35.7 35.7 76.0 18.262.5 21.1 33.3 20.0 0.0 36.4 I_(a)-8 52.4 71.4 76.5 66.7 78.6 50.0 80.093.9 90.6 79.0 71.4 50.0 42.9 54.6 I_(a)-9 38.5 61.5 78.6 36.8 35.7 21.413.7 50.0 84.2 36.4 50.0 45.5 52.6 51.5 I_(a)-10 23.8 35.7 52.9 61.171.4 35.7 68.0 51.5 78.1 36.8 47.6 35.0 39.3 13.6 I_(a)-11 19.1 50.082.4 33.3 35.7 35.7 72.0 60.6 53.1 21.1 38.1 25.0 42.9 63.6 I_(a)-1423.1 84.6 47.6 10.5 14.3 28.6 9.8 18.8 63.2 22.7 25.0 22.7 39.5 12.1I_(a)-15 33.3 21.4 58.8 22.2 78.6 64.3 76.0 66.7 81.3 73.7 66.7 55.017.9 68.2 I_(a)-16 4.8 0.0 23.5 22.2 42.9 28.6 76.0 9.1 53.1 15.8 23.815.0 0.0 4.6 I_(b)-1 19.2 30.8 23.8 21.1 26.2 21.4 7.8 18.8 42.1 22.735.7 27.3 26.3 21.2 I_(b)-2 23.1 61.5 23.8 0.0 21.4 0.0 23.5 15.6 31.69.1 25.0 4.6 29.0 18.2 I_(b)-5 19.2 69.2 11.9 15.8 26.2 42.9 9.8 12.544.7 22.7 35.7 22.7 36.8 21.2 I_(b)-6 26.9 84.6 61.9 26.3 31.0 14.3 29.49.4 63.2 36.4 32.1 27.3 32.9 27.3 I_(b)-7 33.3 42.9 64.7 50.0 42.9 64.360.0 66.7 78.1 42.1 47.6 40.0 42.9 50.0 I_(b)-8 33.3 71.4 64.7 83.3 50.050.0 72.0 51.5 84.4 89.5 38.1 35.0 55.4 50.0 I_(b)-9 19.2 84.6 21.4 26.335.7 14.3 19.6 15.6 44.7 22.7 42.9 22.7 35.5 12.1 I_(b)-10 23.8 21.464.7 55.6 35.7 35.7 56.0 45.5 65.6 31.6 42.9 30.0 21.4 40.9 I_(b)-1123.8 42.9 35.3 55.6 28.6 28.6 76.0 36.4 65.6 15.8 42.9 35.0 17.9 40.9I_(b)-12 19.2 92.3 54.8 26.3 26.2 28.6 17.7 9.4 39.5 18.2 25.0 18.2 42.124.2 I_(b)-13 28.6 50.0 29.4 55.6 21.4 42.9 68.0 60.6 59.4 26.3 38.130.0 33.9 68.2 I_(b)-14 23.1 69.2 33.3 42.1 42.9 28.6 29.4 15.6 65.836.4 42.9 36.4 59.2 36.4 I_(b)-15 13.6 18.2 39.4 9.5 38.5 29.4 30.8 51.554.1 24.0 24.0 26.1 4.2 27.8 I_(b)-16 23.1 84.6 33.3 21.1 14.3 14.3 0.018.8 57.9 18.2 28.6 22.7 46.1 18.2 I_(b)-17 34.6 69.2 47.6 52.6 59.528.6 33.3 37.5 71.1 45.5 50.0 31.8 50.0 27.3 I_(b)-18 23.8 21.4 70.627.8 28.6 35.7 68.0 36.4 53.1 26.3 23.8 5.0 35.7 27.3 I_(b)-19 19.2 41.255.6 25.0 27.6 21.4 35.3 7.9 47.1 24.0 25.9 20.0 26.3 27.3 I_(b)-20 15.423.5 27.8 20.0 24.1 21.4 0.0 18.4 47.1 16.0 18.5 20.0 13.2 36.4 I_(c)-136.4 72.7 36.4 57.1 53.8 58.8 26.9 69.7 86.5 60.0 52.0 30.4 48.6 88.9I_(c)-2 65.4 82.4 97.2 70.0 41.4 57.1 94.1 73.7 98.0 84.0 77.8 76.0 88.286.4 I_(c)-3 38.5 76.5 97.2 65.0 31.0 35.7 41.2 78.9 96.1 64.0 48.1 72.063.2 72.7 I_(c)-4 38.5 58.8 72.2 45.0 58.6 42.9 88.2 78.9 88.2 60.0 48.152.0 59.2 72.7 I_(c)-5 61.5 76.5 97.2 55.0 75.9 64.3 88.2 81.6 94.1 68.077.8 80.0 81.6 59.1 I_(c)-6 27.3 45.5 48.5 42.9 53.8 47.1 46.2 60.6 56.856.0 60.0 39.1 45.8 52.8 I_(c)-7 77.3 72.7 97.0 71.4 76.9 70.6 84.6 84.897.3 80.0 80.0 65.2 62.5 80.6 I_(c)-8 23.1 64.7 72.2 30.0 65.5 64.3 94.173.7 84.3 68.0 55.6 52.0 59.2 59.1 I_(c)-9 34.6 58.8 69.4 65.0 41.4 57.188.2 81.6 92.2 48.0 40.7 40.0 68.4 68.2 I_(c)-10 26.9 23.5 88.9 45.072.4 21.4 64.7 63.2 78.4 56.0 40.7 44.0 32.9 77.3 I_(c)-11 22.7 45.566.7 52.4 30.8 47.1 21.2 84.8 89.2 52.0 72.0 30.4 44.4 66.7 I_(c)-1231.8 63.6 63.6 52.4 53.8 58.8 44.2 81.8 86.5 56.0 48.0 39.1 50.0 88.9I_(c)-13 22.7 45.5 66.7 52.4 30.8 47.1 21.2 84.8 89.2 52.0 72.0 30.444.4 66.7 I_(c)-14 19.2 47.1 77.8 30.0 10.3 28.6 88.2 84.2 86.3 56.048.1 44.0 28.9 72.7 I_(c)-15 23.1 35.3 52.8 15.0 27.6 21.4 64.7 28.966.7 28.0 29.6 24.0 23.7 36.4 I_(c)-16 38.5 41.2 83.3 15.0 62.1 50.035.3 26.3 80.4 32.0 40.7 52.0 39.5 54.5 I_(c)-17 23.1 23.5 75.0 20.020.7 21.4 5.9 18.4 41.2 16.0 25.9 12.0 21.1 36.4 I_(c)-18 11.5 52.9 69.435.0 6.9 28.6 64.7 39.5 68.6 20.0 33.3 36.0 32.9 81.8 I_(c)-19 23.1 23.597.2 15.0 41.4 14.3 58.8 42.1 74.5 28.0 29.6 24.0 32.9 22.7 I_(c)-2026.9 47.1 55.6 45.0 62.1 28.6 88.2 68.4 72.5 44.0 44.4 36.0 46.1 72.7I_(c)-21 34.6 47.1 97.2 15.0 27.6 28.6 35.3 18.4 64.7 12.0 25.9 24.015.8 36.4 I_(c)-22 26.9 29.4 52.8 30.0 20.7 14.3 41.2 31.6 64.7 36.022.2 32.0 6.6 40.9 I_(c)-23 19.2 17.6 69.4 45.0 6.9 0.0 64.7 5.3 43.112.0 14.8 20.0 6.6 9.1 I_(c)-24 9.1 36.4 24.2 19.0 61.5 35.3 46.2 18.229.7 36.0 32.0 17.4 22.2 44.4 I_(c)-25 4.5 0.0 33.3 19.0 30.8 41.2 21.29.1 29.7 36.0 24.0 17.4 5.6 66.7 I_(c)-26 4.5 18.2 36.4 19.0 46.2 29.415.4 12.1 48.6 20.0 24.0 17.4 8.3 36.1 I_(c)-27 0.0 36.4 39.4 33.3 61.529.4 11.5 36.4 51.4 36.0 52.0 26.1 15.3 69.4 I_(c)-28 4.5 36.4 36.4 14.353.8 23.5 3.8 18.2 48.6 28.0 32.0 30.4 8.3 41.7 I_(c)-29 0.0 18.2 9.119.0 46.2 29.4 7.7 12.1 48.6 32.0 32.0 26.1 15.3 52.8 I_(d)-1 13.6 18.251.5 19.0 61.5 47.1 26.9 27.3 43.2 36.0 32.0 17.4 1.4 44.4 I_(d)-2 4.518.2 39.4 14.3 53.8 29.4 19.2 6.1 45.9 28.0 24.0 30.4 0.0 61.1 I_(d)-313.6 27.3 39.4 14.3 53.8 29.4 3.8 15.2 18.9 16.0 36.0 26.1 15.3 55.6I_(d)-4 13.6 27.3 45.5 33.3 38.5 29.4 7.7 18.2 35.1 28.0 32.0 17.4 5.655.6 I_(d)-5 22.7 45.5 63.6 23.8 46.2 29.4 26.9 21.2 29.7 32.0 28.0 26.11.4 66.7 I_(d)-6 4.5 9.1 42.4 14.3 30.8 29.4 17.3 12.1 10.8 20.0 24.026.1 5.6 50.0 I_(d)-7 9.1 9.1 33.3 9.5 15.4 29.4 7.7 15.2 29.7 28.0 16.021.7 1.4 50.0 Carbendazim <50 <50 <50 <50 100 <50 100 <50 100 100 100100 100 <50 Chlorothalonil 100 73.3 100 73.3 <50 100 <50 100 100 91.391.3 86.4 100 100

Table 2 indicates most of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloids and their derivatives (I_(a), I_(b),I_(c) and I_(d)) show high bactericidal activity against 14 kinds offungi, and particularly, compound I_(a)-1, I_(c)-2, I_(c)-5 and I_(c)-7show very good bactericidal activity against various kinds of fungi.

Embodiment 23: Determination of Activity Against Armyworms, CottonBollworms and Corn Borers. The Determination Procedure is as Follows

Test of Activity Against Cotton Bollworms

Experimental method of cotton bollworms: feed and drug mixing method:measure 3 mL of prepared solution and add it to about 27 g of newlyprepared feed, thereby obtaining needed concentration through dilutionby 10 times. Pour the evenly mixed drug into clean 24-well plates, coolit in the air, put 24 third instar cotton bollworms, observe them for3-4 days and then check results.

Test of Activity Against Armyworms

Experimental method of armyworms: leaf soaking method: prepare a drugsolution at the needed concentration, soak leaves with a diameter ofabout 5-6 cm in the drug solution for 5-6 s, take them out, put them onabsorbent paper, dry them in the air, put them in a designated culturedish, put 10 third instar larvae, transfer them to a 27±1° C.insectariums, observe them for 3-4 days and then check results.

Test of Activity Against Corn Borers

Experimental method of corn borers: leaf soaking method: prepare a drugsolution at the needed concentration, soak leaves with a diameter ofabout 5-6 cm in the drug solution for 5-6 s, take them out, put them onabsorbent paper, dry them in the air, put them in a designated culturedish, put 10 third instar larvae, transfer them to a 27±1° C.insectariums, observe them for 3-4 days and then check results.

TABLE 3 Test results of the activity of some of β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloids and theirderivatives (I_(a), I_(b), I_(c) and I_(d)) against armyworms, cottonbollworms and corn borers: Armyworm Cotton bollworm Corn borerConcentration Mortality Concentration Mortality Concentration MortalityNo. (mg/kg) (%) (mg/kg) (%) (mg/kg) (%) Harmalan 600 20 600 10 600 15Tetrahydroharmane 600 15 600 15 600 10 Harmane 600 45 600 35 600 35Tetrahydroharmine 600 0 600 10 600 0 Harmine 600 20 600 15 600 15 Harmol600 50 600 20 600 45 I_(a)-1 600 30 600 20 600 25 I_(a)-3 600 50 600 35600 50 I_(a)-4 600 10 600 10 600 5 I_(a)-5 600 10 600 15 600 10 I_(a)-6600 45 600 20 600 35 I_(a)-7 600 35 600 30 600 25 I_(a)-8 600 70 600 15600 65 I_(a)-9 600 5 600 20 600 5 I_(a)-10 600 30 600 40 600 30 I_(a)-11600 10 600 10 600 10 I_(a)-14 600 25 600 30 600 20 I_(a)-15 600 15 60015 600 5 I_(a)-16 600 10 600 5 600 10 I_(b)-1 600 25 600 25 600 25I_(b)-2 600 10 600 25 600 10 I_(b)-5 600 50 600 30 600 35 I_(b)-6 600 45600 20 600 40 I_(b)-7 600 5 600 20 600 5 I_(b)-8 600 5 600 20 600 0I_(b)-9 600 15 600 10 600 10 I_(b)-10 600 30 600 15 600 25 I_(b)-11 6005 600 20 600 5 I_(b)-12 600 50 600 30 600 50 I_(b)-13 600 60 600 30 60055 I_(b)-14 600 10 600 30 600 10 I_(b)-15 600 20 600 20 600 30 I_(b)-16600 65 600 50 600 50 I_(b)-17 600 45 600 30 600 40 I_(b)-18 600 5 600 5600 5 I_(b)-19 600 5 600 60 600 10 I_(b)-20 600 65 600 30 600 60 I_(c)-1600 75 600 55 600 60 I_(c)-2 600 10 600 30 600 5 I_(c)-3 600 25 600 40600 30 I_(c)-4 600 30 600 35 600 35 I_(c)-5 600 25 600 25 600 20 I_(c)-6600 45 600 35 600 40 I_(c)-7 600 5 600 30 600 5 I_(c)-8 600 20 600 35600 15 I_(c)-9 600 35 600 30 600 40 I_(c)-10 600 25 600 30 600 30I_(c)-11 600 65 600 40 600 55 I_(c)-12 600 15 600 30 600 15 I_(c)-13 60030 600 15 600 35 I_(c)-14 600 40 600 35 600 45 I_(c)-15 600 15 600 15600 20 I_(c)-16 600 20 600 10 600 30 I_(c)-17 600 25 600 20 600 20I_(c)-18 600 10 600 20 600 15 I_(c)-19 600 70 600 50 600 60 I_(c)-20 60035 600 20 600 30 I_(c)-21 600 40 600 45 600 35 I_(c)-22 600 40 600 20600 50 I_(c)-23 600 15 600 10 600 10 I_(c)-24 600 45 600 20 600 50I_(c)-25 600 45 600 20 600 55 I_(c)-26 600 25 600 20 600 30 I_(c)-27 60020 600 30 600 30 I_(c)-28 600 45 600 45 600 40 I_(c)-29 600 20 600 25600 15 I_(d)-1 600 35 600 15 600 35 I_(d)-2 600 40 600 40 600 40 I_(d)-3600 25 600 40 600 25 I_(d)-4 600 10 600 30 600 15 I_(d)-5 600 5 600 30600 25 I_(d)-6 600 35 600 25 600 50 I_(d)-7 600 40 600 30 600 40

Table 3 indicates most of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloids and their derivatives (I_(a), I_(b),I_(c) and I_(d)) show certain activity against armyworms, cottonbollworms and corn borers. Particularly, compounds I_(a)-8, I_(b)-13,I_(b)-16, I_(b)-20, I_(c)-1, I_(c)-11 and I_(c)-19 show broad-spectrumactivity.

Embodiment 24: Determination of Activity Against Mosquito Larvae, andthe Determination Procedure is as Follows

Test of Activity Against Mosquito Larvae

Experimental method of mosquito larvae: culex pipiens pallens, a normalcolony raised indoors. Weigh about 5 mg of the compound for test, put itin a penicillin vial, add 5 mL of acetone (or an appropriate solvent),and shake and dissolve it to obtain a 1000 ppm mother solution. Pipette0.5 mL of the mother solution, add it to a 100 mL beaker filled with89.9 mL of water, select 10 mosquito larvae at the beginning of thefourth instar, and pour them to a beaker together with 10 mL of feedingsolution. The concentration of the drug solution is 5 ppm. Put it in astandard treatment room and check the result 24 h later. Use an aqueoussolution containing 0.5 mL of test solvent as a blank.

TABLE 4 Test results of the activity of some of β-carboline,dihydro-β-carboline and tetrahydro-β-carboline alkaloids and theirderivatives (I_(a), I_(b), I_(c) and I_(d)) against mosquito larvae:Mosquito larvae Larvae Concen- Concen- tration Mortality trationMortality No. (mg/kg) (%) No. (mg/kg) (%) Harmalan 10 35 I_(b)-19 10 20Tetrahydroharmane 10 30 I_(b)-20 10 100 Harmane 10 100 5 40 5 10 I_(c)-110 100 Tetrahydroharmine 10 15 5 80 Harmine 10 45 I_(c)-2 10 20 Harmol10 100 I_(c)-3 10 55 5 30 I_(c)-4 10 65 I_(a)-1 10 50 I_(c)-5 10 50I_(a)-3 10 100 I_(c)-6 10 100 5 60 5 20 I_(a)-4 10 30 I_(c)-7 10 10I_(a)-5 10 30 I_(c)-8 10 35 I_(a)-6 10 100 I_(c)-9 10 75 5 20 I_(c)-1010 50 I_(a)-7 10 65 I_(c)-11 10 100 I_(a)-8 10 100 5 40 5 60 I_(c)-12 1015 I_(a)-9 10 25 I_(c)-13 10 60 I_(a)-10 10 65 I_(c)-14 10 75 I_(a)-1110 50 I_(c)-15 10 30 I_(a)-14 10 35 I_(c)-16 10 40 I_(a)-15 10 35I_(c)-17 10 50 I_(a)-16 10 20 I_(c)-18 10 25 I_(b)-1 10 55 I_(c)-19 10100 I_(b)-2 10 30 5 80 I_(b)-5 10 100 I_(c)-20 10 75 5 30 I_(c)-21 10 85I_(b)-6 10 100 I_(c)-22 10 85 5 20 I_(c)-23 10 35 I_(b)-7 10 15 I_(c)-2410 100 I_(b)-8 10 10 5 10 I_(b)-9 10 35 I_(c)-25 10 100 I_(b)-10 10 60 510 I_(b)-11 10 15 I_(c)-26 10 55 I_(b)-12 10 100 I_(c)-27 10 40 5 40I_(c)-28 10 100 I_(b)-13 10 100 5 20 5 60 I_(c)-29 10 45 I_(b)-14 10 30I_(d)-1 10 75 I_(b)-15 10 40 I_(d)-2 10 80 I_(b)-16 10 100 I_(d)-3 10 505 60 I_(d)-4 10 25 I_(b)-17 10 100 I_(d)-5 10 10 5 10 I_(d)-6 10 65I_(b)-18 10 10 I_(d)-7 10 80

Table 4 indicates most of β-carboline, dihydro-β-carboline andtetrahydro-β-carboline alkaloids and their derivatives (I_(a), I_(b),I_(c) and I_(d)) show high activity against culex pipiens larvae, andI_(a)-3, I_(a)-8, I_(b)-13, I_(b)-16, I_(c)-1 and I_(c)-19 still showhigh activity at 5 mg/kg.

The invention claimed is:
 1. A β-carboline compound with a structureshown in the following formula Ic or formula Id

wherein, R⁴ and R⁵ respectively represent hydrogen, C1-C10 alkyl, C3-C10nitrogen-containing heterocyclic ring, C1-C10 oxygen-containingheterocyclic ring, or C1-C10 sulfur-containing heterocyclic ring, or R⁴and R⁵ form a C6 aliphatic ring, or R⁴ is hydrogen and R⁵ isprop-2-enyl; and R⁶ represents hydrogen, hydroxy, C1-C6 alkoxy,substituted phenyl ring, C1-C10 oxygen-containing heterocyclic ring, orC1-C10 sulfur-containing heterocyclic ring.
 2. A β-carboline compoundselected from the group consisting of: (1S,3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-1); (1S, 3S)—N′-(4-tert-butylbenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-2); (1S, 3S)—N′-(4-dimethyl aminobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-3); (1S,3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-4); (1S,3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-5); (1S, 3S)—N′-(2,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-6); (1S,3S)—N′-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-7); (1S,3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-8); (1S,3S)—N′-(3-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-9); (1S,3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-10); (1S,3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-11); (1S, 3S)—N′-((benzo [d] [1,3] dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-12); (1S, 3S)—N′-(2,3-dihydrobenzo [b] [1, 4]dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-13); (1S,3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-14); (1S,3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-15); (1S,3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-16); (1S,3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-17); (1S,3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-18); (1S,3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-19); (1S,3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-20); (1S,3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-21); (1S,3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-22); (1S,3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-23); (1S,3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-24); (1S,3S)—N′-(cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-25); (1S,3S)—N′-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-26); (1S,3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-27); (1S,3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-28); (1S,3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-29); N′-((1S,3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-tricarboxylate)benzo [d] [1,2,3] thiadiazole-7-formylhydrazine (I_(d)-i);4-methyl-N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-triformyl)-1, 2, 3-thiadiazole-5-formylhydrazine (I_(d)-2); (1S,3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-3); (1S,3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-4); (1S,3S)—N′-n-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-5); (1S,3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-G); and (1S, 3S)—N′-(cyclopentylformyl)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-7).
 3. A method for preparing theβ-carboline according to claim 2: regarding I_(c)-1-I_(c)-29, the methodcomprising: reacting hydrazide compound I_(b)-15 with fatty aldehyde oraromatic aldehyde to obtain corresponding acylhydrazone compoundI_(c)-1-I_(c)-29:

regarding I_(d)-1-I_(d)-7, the method comprising: reacting hydrazidecompound I_(b)-15 with acyl chloride to obtain correspondingbishydrazide compound I_(d)-1-I_(d)-7:


4. A method of treating plant viruses comprising administering theβ-carboline compound according to claim
 1. 5. A method of treating plantviruses comprising administering a β-carboline compound selected fromthe group consisting of: (1S,3S)—N′-benzylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-1); (1S, 3S)—N′-(4-tert-butylbenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-2); (1S, 3S)—N′-(4-dimethyl aminobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-3); (1S,3S)—N′-(4-nitrobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-4); (1S,3S)—N′-(4-chlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-5); (1S, 3S)—N′-(2,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-6); (1S,3S)—N′-(3,4-dichlorobenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-7); (1S,3S)—N′-(4-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-8); (1S,3S)—N′-(3-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-9); (1S,3S)—N′-(2-methoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-10); (1S,3S)—N′-(3,4-dimethoxybenzylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-11); (1S, 3S)—N′-((benzo [d] [1,3] dioxymethylene-5)-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-12); (1S, 3S)—N′-(2,3-dihydrobenzo [b] [1, 4]dioxin-6-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-13); (1S,3S)—N′-(6-hydroxynaphthalene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-14); (1S,3S)—N′-(pyridine-4-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-15); (1S,3S)—N′-(pyridine-3-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-16); (1S,3S)—N′-(pyridine-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-17); (1S,3S)—N′-(furan-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-18); (1S,3S)—N′-(pyrrole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-19); (1S,3S)—N′-(thiophene-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-20); (1S,3S)—N′-(imidazole-2-methylene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-21); (1S,3S)—N′-((E)-but-2-enylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-22); (1S,3S)—N′-butylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-23); (1S,3S)—N′-octadien-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-24); (1S,3S)—N′-(cyclohexylmethylene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-25); (1S,3S)—N′-(2,2-dimethylpropylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-26); (1S,3S)—N′-(1-phenylethylidene)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-27); (1S,3S)—N′-(3,3-dimethyl-2-butylidene)-1-methyl-2,3,4,9-tetrahydropyridino[3,4-b] indol-3-formylhydrazine (I_(c)-28); (1S,3S)—N′-cyclohexylidene-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(c)-29); N′-((1S,3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b] indol-3-tricarboxylate)benzo [d] [1,2,3] thiadiazole-7-formylhydrazine (I_(d)-1);4-methyl-N′-((1S, 3S)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-triformyl)-1, 2, 3-thiadiazole-5-formylhydrazine (I_(d)-2); (1S,3S)—N′-isonicotinoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-3); (1S,3S)—N′-benzoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-4); (1S,3S)—N′-n-hexanoyl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-5); (1S,3S)—N′-tert-valeryl-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-f ormylhydrazine (I_(d)-6); and (1S, 3S)—N′-(cyclopentylformyl)-1-methyl-2,3,4,9-tetrahydropyridino [3,4-b]indol-3-formylhydrazine (I_(d)-7).
 6. The method according to claim 4,wherein the compound effectively inhibits tobacco mosaic virus, chillivirus, rice virus, tomato virus, sweet potato virus, potato virus andcucurbits virus as well as maize dwarf mosaic virus; the compound showsbactericidal activity against 14 kinds of pathogenic bacteria, which arecucumber fusarium wilt, Cercospora arachidicola, Macrophoma kawatsukai,Alternaria solani, Fusarium graminearumt, potato late blight,Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani,Phytophthora capsici, Fusarium fujikuroi, Rhizoctonia cereali, Bipolariamaydis and Colletotrichum orbiculare; the compound shows activityagainst armyworms, cotton bollworms, corn borers and culex pipiens. 7.The method according to claim 5, wherein the compound effectivelyinhibits tobacco mosaic virus, chilli virus, rice virus, tomato virus,sweet potato virus, potato virus and cucurbits virus as well as maizedwarf mosaic virus; the compound shows bactericidal activity against 14kinds of pathogenic bacteria, which are cucumber fusarium wilt,Cercospora arachidicola, Macrophoma kawatsukai, Alternaria solani,Fusarium graminearumt, potato late blight, Sclerotinia scleotiorum,Botrytis cinerea, Rhizoctonia solani, Phytophthora capsici, Fusariumfujikuroi, Rhizoctonia cereali, Bipolaria maydis and Colletotrichumorbiculare; the compound shows activity against armyworms, cottonbollworms, corn borers and culex pipiens.
 8. The method according toclaim 3, wherein the method for preparing I_(b)-15 comprises the stepsof: reacting methyl ester I_(b)-7 with hydrazine hydrate (80%) to obtaincompound I_(b)-15:


9. The method according to claim 8, wherein the method for preparingI_(b)-7 comprises the steps of: reacting L-tryptophan with anacetaldehyde aqueous solution to obtain cyclization product I_(b)-1,which is then further esterified by one step to obtain compound I_(b)-7,